Amidino derivatives and drugs containing the same as the active ingredient

ABSTRACT

The novel amidino derivatives of the formula (I):                    
     wherein all the symbols are as in specification defined; 
     have an inhibitory activity of a blood coagulation factor VIIa and are useful for treatment and/or prevention of several angiopathy caused by enhancing a coagulation activity, such as disseminated intravascular coagulation, coronary thrombosis, cerebral infarction, cerebral embolism, transient ischemic attack, cerebrovascular disorders, pulmonary vascular diseases, deep venous thrombosis, peripheral arterial obstruction, thrombosis after artificial vascular transplantation and artificial valve transplantation, post-operative thrombosis, reobstruction and restenosis after coronary artery bypass operation, reobstruction and restenosis after PTCA or PTCR, thrombosis by extracorporeal circulation and procoagulative diseases such as glomerlonephriitis.

This application is a 371 of PCT/JP99/0062 filed Feb. 12, 1999.

TECHNICAL FIELD

This invention is related to amidino derivatives of the formula (I),non-toxic salts thereof, hydrates thereof, processes for the preparationthereof, and the blood coagulation factor VIIa inhibitors containing thederivatives as active ingredient.

More particularly, this invention is related to amidino derivatives ofthe formula (I)

wherein all the symbols are as hereinafter defined, non-toxic saltsthereof, hydrates thereof, processes for the preparation thereof, andthe blood coagulation factor VIIa inhibitors containing the derivativesas active ingredient.

BACKGROUND ART

The blood coagulation is a protective reaction which is caused byvascular injury or irritate stimulus with endotoxin or the other foreignbodies. This reaction proceeds on the membrane of platelets whichaggregate at the injured site or on the membrane of injured endothelialcells and it requires Ca ion. The blood coagulation system containseight kinds of serine proenzymes (e.g. plasma prekallikrein factor XII,factor XI, factor VII, factor IX, factor X, prothrombin, protein C),five protein co-factor (e.g. macromolecule kininogen, tissue factor,factor VIII, factor V, protein S), and a fibrillar protein, fibrinogen.α-Thrombin produced by the coagulation cascade give information toendothelial cells and form insoluble fibrin gel. The scheme of the bloodcoagulation cascade is shown below.

The blood coagulation cascade consists of the intrinsic pathway and theextrinsic pathway. The intrinsic pathway acts on foreign surface chargednegatively. However, foreign surface in the body is uncertain, so thesignificance of the intrinsic pathway in hemostasis is not established.On the other hand, the extrinsic pathway is triggered by the complexformation of the blood coagulation factor VIIa (FVIIa) and tissue factorwhich is expressed by a vascular damage or the presence of endotoxin.This pathway confluents with the intrinsic pathway at a point of factorX and factor IX activation.

The extrinsic pathway seems to be more important than the intrinsicpathway in the physiologic condition (hemostasis) or pathologicalcondition (thrombosis). The reasons are as follows.

1) The presence of tissue factor (TF) is recognized in physiologicalcondition.

2) The expression of TF is induced by endotoxin on the membrane ofvascular endothelial cells or/and monocytes.

3) Since TF is observed on foam cells in the plaque of arteriosclerosis,the extrinsic pathway is considered to contribute the topicalcoagulation activity.

Warfarin, an anticoagulant agent, inhibits the production of variousfactors, including protein C and S. Thrombin inhibitors such as heparin,which act at the downstream of a coagulation cascade, may inhibit bloodcoagulation excessively and do not inhibit the consumption ofcoagulation factors. Because of these reasons, bleeding tendency is themain problem in clinic.

On the other hand, FVIIa is located at the top site of the cascade inthe extrinsic pathway. Therefore, FVIIa inhibitors inhibit the extrinsicpathway, leaving intact the activity of the intrinsic pathway.

Consequently, FVIIa inhibitors are different from thrombin inhibitorsleaving a function of the intrinsic pathway. It is considered that FVIIainhibitors have a resistance to bleeding, then it is expected to be ableto reduce a bleeding tendency as a side effect.

FVIIa inhibitors suppress a coagulation activity of the extrinsicpathway, and then they are useful for treatment and/or prevention forseveral thormbotic diseases triggered by the extrinsic pathway. Forexample, several angiopathy caused by enhancing a coagulation activity,such as disseminated intravascular coagulation, coronary thrombosis(e.g. acute myocardial infarction, unstable angina), cerebralinfarction, cerebral embolism, transient ischemic attack,cerebrovascular disorders, pulmonary vascular diseases (e.g. pulmonaryinfarction, pulmonary embolism), deep venous thrombosis, peripheralarterial obstruction, thrombosis after artificial vasculartransplantation and artificial valve transplantation, post-operativethrombosis, reobstruction and restenosis after coronary artery bypassoperation, reobstruction and restenosis after PTCA (percutaneoustransluminal coronary angioplasty) or PTCR (percutaneous transluminalcoronary recanalization), thrombosis by extracorporeal circulation andprocoagulative diseases such as glomerlonephriitis.

(1) In the specification of WO 9620689, boric acid derivatives of theformula (A):

R^(1A)—Z^(A)—CHR^(2A)—A^(A)  (A)

wherein A^(A) is —BY^(1A)Y^(2A), in which Y^(A1) and y^(2A) eachindependently, is —OH, C1-8 alkoxy; —COOR^(3A), in which R^(3A) ishydrogen, C1-8 alkyl; R^(2A) is

in which pA is 0-2, qA is 0-4, X^(A) is C(NH)NHR^(14A), in which R^(14A)is hydrogen, C1-4 alkyl; Z^(A) is (CH₂)_(mA)CONR^(8A),(CH₂)_(mA)CSNR^(8A), (CH₂)_(mA)SO₂NR^(8A), (CH₂)_(mA)CO₂, (CH₂)_(mA)CSO,(CH₂)_(mA)SO₂O, R^(8A) is hydrogen, C1-8 alkyl, mA is 0-6, R^(1A) is(CH₂)_(PA)aryl, in which pA is 0-2, aryl is phenyl, naphthyl, biphenyl,and they may be substituted by 1-3 of (CH₂)_(WA)CO₂R^(8A),(CH₂)_(WA)CNR^(8A)R^(9A); WA is 0-5, R^(8A) and R^(9A) is hydrogen, C1-8alkyl; with the proviso that explanations of each inhibitory activity ofthrombin, Fxa, FVIIa.

(2) In the specification of WO 9429273, the compound of the formula (B):

wherein A^(1B) to A^(4B) form a substituted 6 membered ring optionallyunsaturated, and optionally containing up to two hetero atoms selectedfrom O, S and N;

D^(1B) to D^(4B) form a substituted 6 membered aromatic ring optionallycontaining up to two nitrogens, D^(1B)-D^(4B) is CR^(11B) or N; R^(B) isat least one substituent selected from R⁷, Q^(B)—C1-4 alkyl, Q^(B)—C2-4alkenyl and Q^(B)—C2-4 alkynyl;

R^(*B) is hydrogen, Q^(B)—C1-6 alkyl, Ar^(B) or Het^(B);

Q^(B) is hydrogen, C3-6 cycloalkylHet^(B) or Ar^(B);

R^(6B) isW^(B)—(CR′^(B2))q^(B)—Z^(B)—(CR′^(B)R^(10B))r^(B)—U^(B)—(CR′^(B2))s^(B)—V^(B)—;

R^(7B) is —COR^(8B), —PO(OR′^(B))₂ and Tet^(B);

R^(8B) is —OR′^(B), —NR′^(B)R″^(B), —NR′^(B)OR′^(B);

R^(10B) is hydrogen, C1-4 alkyl or —NR′^(B)R″^(B);

R^(11B) is Q^(B)—C0-6 alkyl;

R′^(B), R″^(B) are hydrogen, C1-6 alkyl, C3-7 cycloalkyl-C0-4 alkyl, orAr^(B)—C0-4 alkyl;

UB and VB is absent or CONR′^(B), NR′^(B)CO, S(O)_(nB)NR′^(B),NR′^(B)S(O)_(nB), NR′^(B)CR′^(B) ₂,

CR′^(B) ₂NR′^(B), CR′^(B) ₂O, OCR′^(B) ₂, C≡C, CR′^(B)═CR′^(B);

W^(B) is

Y^(B) is absent, S or O;

Z^(B) is (CH₂)_(tB), Het^(B), Ar^(B) or C3-7 cycloalkyl;

nB is 0-3; qB is 0-3; rB is 0-2; sB is 0-2; tB is 0-2; with the provisothat explanations of each groups were disclosed only necessary parts; orsalts thereof are described to possible an inhibitory activity offibrinogen receptor GPIIb/IIIa.

In the specification of WO 9300095 and WO 9412478, similarity compoundsare described to possible an inhibitory activity of fibrinogen receptorGPIIb/IIIa.

(3) In the specification of WO 9730971, the compound of the formula (C):

wherein D^(C) is CN, C(=NR7^(C))NR^(8C)R^(9C),NHC(=NR^(7C))N^(R8)CR^(9C), NR^(8C)CH(=NR^(7C)) etc.; E^(C) is phenyl,2-pyridyl, 4-pyridyl, etc.; R^(aC) is a single bond or CH═CH; R^(bC) isC(O)R^(C) or G^(C); G^(C) is hydrogen, OG^(1C), SG^(1C), NG^(1C)G^(2C),etc.; G^(1C) is hydrogen, C1-6 alkyl; G^(2C) is hydrogen, C1-6 alkyl;R^(C) is hydrogen, OH, C1-6 alkoxy, etc.; R^(7C) is hydrogen, OH, C1-6alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, etc.;R^(8C) and R^(9C) are hydrogen, C1-6 alkyl, (CH₂)_(n)-phenyl; X^(C) isCHCH(R^(1C)), N, etc.; Z^(C) is (CH₂)_(n), C(═O), etc.; p^(C) is 1-4;A^(C) is benzyl, C3-10 carbocyclic ring, 5-10 membered heterocyclicring; B^(C) is hydrogen, C1-6 alkyl, benzyl, C3-10 carbocyclic ring,5-10 membered heterocyclic ring; are described to possible an inhibitoryactivity of FXa.

DISCLOSURE OF INVENTION

Energetic investigations have been carried out in order to make theblood coagulation factor VIIa inhibitors. The present inventors havefound that the present compound of the formula (I) accomplished thepresent purpose.

The present invention is related to amidino derivatives of the formula(I):

wherein R¹ and R² each independently, is

1) hydrogen,

2) hydroxy,

3) C1-4 alkoxycarbonyl,

4) C2-4 alkenyloxycarbonyl,

5) C1-4 alkoxycarbonyloxy or

6) —COO—(C1-4 alkyl)-phenyl,

 when R² is group excepting hydrogen, R² is hydrogen, or when R² isgroup excepting hydrogen, R¹ is hydrogen;

R³ is

1) hydrogen,

2) C1-4 alkyl,

3) hydroxy,

4) —O—(C1-4 alkyl)-phenyl, or

5) halogen atom;

E¹ ring is

1) 5-7 membered unsaturated carbocyclic ring or

2) 5-7 membered unsaturated heterocyclic ring;

E² ring is

1) 5-7 membered unsaturated carbocyclic ring or

2) 5-7 membered unsaturated heterocyclic ring;

E³ ring is

1) absent,

2) 5-7 membered unsaturated or saturated carbocyclic ring or

3) 5-7 membered unsaturated or saturated heterocyclic ring;

E⁴ ring is

1) 5-6 membered unsaturated carbocyclic ring or

2) 5-6 membered unsaturated heterocyclic ring;

R⁴ and R⁵ each independently is

1) —COOR⁸, in which R⁸ is hydrogen, C1-8 alkyl, —(C1-4 alkyl)-phenyl or—(C1-4 alkyl)—O—(C1-4 alkyl);

2) —(C1-4 alkyl)—COOR⁹, in which R⁹ is hydrogen, C1-8 alkyl, —(C1-4alkyl)-phenyl or —(C1-4 alkyl)—O—(C1-4 alkyl);

3) —(C2-4 alkenyl)-COOR¹⁰, in which R¹⁰ is hydrogen, C1-8 alkyl,—(C1-4alkyl)-phenyl or —(C1-4 alkyl)—O—(C1-4 alkyl);

4) —O—(C1-4 alkyl)-COOR¹¹, in which R¹¹ is hydrogen, C1-8 alkyl, —(C1-4alkyl)-phenyl or —(C1-4 alkyl)—O—(C1-4 alkyl);

5) —CONR¹²R¹³, in which R¹² is hydrogen, C1-4 alkyl, R¹³ is hydroxy,—O—(C1-4 alkyl)-phenyl or cyano;

6) —P(O)(OR¹⁴)₂, in which R¹⁴ is hydrogen, C1-4 alkyl or —(C1-4alkyl)-phenyl; or

7) tetrazol-5-yl which is optionally substituted by C1-8 alkyl; p and qeach independently, is 0 or 1-2, with the proviso that p+q is 1 or 2;

R⁶ and R⁷ each independently, is

1) hydrogen,

2) C1-8 alkyl,

3) nitro,

4) cyano,

5) halogen atom,

6) —(C1-4 alkyl)—O—(C1-4 alkyl)-phenyl,

7) —NR¹⁵R¹⁶, in which R¹⁵ and R¹⁶ each independently, is hydrogen orC1-8 alkyl;

8) —OR¹⁷, in which R¹⁷ is hydrogen, C1-8 alkyl, CF₃, C2-5 acyl, —(C1-4alkyl)-phenyl, —(C1-4 alkyl)—OH, —(C1-4 alkyl)—O—(C1-4 alkyl), or —(C1-4alkyl)—O—(C1-4 alkyl)—O—(C1-4 alkyl);

9) —(C1-4 alkyl)—OR¹⁷, in which R¹⁷ is as hereinbefore defined

10) —J¹—J², in which J¹ is

(1) —CONR¹⁸—, in which R¹⁸ is hydrogen or C1-4 alkyl;

(2) —NR¹⁹CO—, in which R¹⁹ is hydrogen or C1-4 alkyl;

(3) —SO₂NR²⁰—, in which R²⁰ is hydrogen or C1-4 alkyl;

(4) —NR²¹SO₂—, in which R²¹ is hydrogen or C1-4 alkyl;

(5) —(C1-4 alkyl)—NR²²—, in which R²² is hydrogen or C1-4 alkyl;

(6) —CO—,

(7) —(C1-4 alkyl)—NR²³CO—, in which R²³ is hydrogen or C1-4 alkyl;

J² is

(1) C1-15 alkyl optionally substituted by 1-3 of following groups(i)-(x):

(i) C3-7 cycloalkyl optionally substituted by —(C1-4 alkyl)—OR²⁴;

(ii) phenyl,

(iii) 5-7 saturated heterocyclic ring optionally substituted by carboxylor C1-4 alkoxycarbonyl;

(iv) OR²⁴, in which R²⁴ is hydrogen, C1-4 alkyl, —COO—(C1-4alkyl)-phenyl, C2-5 acyl, or —(C1-4 alkyl)-phenyl;

(v) NR²⁵R²⁶, in which R²⁵ is hydrogen or C1-4 alkyl, R²⁶ is hydrogen,C1-4 alkyl, —COO(C1-4 alkyl)-phenyl, imino(C1-4 alkyl) or C1-4alkoxycarbonyl;

(vi) —S(O)_(r)—(C1-4 alkyl), in which r is 0-2;

(vii) —COOR²⁷, in which R²⁷ is hydrogen, C1-4 alkyl or —(C1-4alkyl)-phenyl;

(viii) —CONR²⁸R²⁹, in which R²⁸ and R²⁹ each independently, is

 (i) hydrogen, (ii) C1-4 alkyl, (iii) hydroxy, or (iv) C1-4 alkylsubstituted by one of hydroxy, phenyl or NR²⁵R²⁶, or R²⁸ and R²⁹ takentogether with the nitrogen atom to which they are attached form 5-6membered saturated heterocyclic ring containing nitrogen atom;

(ix) halogen atom,

(x) trihalomethyl;

(2) C2-8 alkenyl,

(3) C5-7 cycloalkyl optionally substituted by 1-3 of C1-4 alkyl,—COOR²⁷, in which R²⁷ is as hereinbefore defined; —(C1-4 alkyl)—OR²⁴, inwhich R²⁴ is as hereinbefore defined;

(4) —NR²⁵R²⁶, in which R²⁵ and R²⁶ is as hereinbefore defined;

(5) 5-6 membered saturated heterocyclic ring optionally substituted by1-3 of C1-4 alkyl, oxo, imino(C1-4 alkyl); or R¹⁸ and J² taken togetherwith the nitrogen atom to which they are attached form saturatedheterocyclic ring optionally substituted by 1-3 of C1-8 alkyl, C2-8alkenyl or —COOR²⁷, in which R²⁷ is hereinbefore defined;

m is 1-3;

n is 1-3;

two R⁶ taken together with the neighboring two carbon of E⁴ ring towhich they are attached form 5-6 membered unsaturated carbocyclic ringor 5-6 membered saturated heterocyclic ring, that rings may besubstituted by 1-3 of R⁴ or R⁶;

A is

1) ethylene,

2) vinylene,

3) ethynylene,

4) —O—CH₂—,

5) —CH₂—O—,

6) —NR³⁰CO—, in which R³⁰ is hydrogen or C1-4 alkyl;

7) —NR³¹CHR³²—, in which R³¹ is hydrogen or C1-4 alkyl, R³² is hydrogen,cyano, COOR³⁶, in which R³⁶ is hydrogen or C1-4 alkyl; or CONR³⁷R³⁸, inwhich R³⁷ and R³⁸ each independently, is hydrogen or C1-4 alkyl;

8) —CH₂—NR³³—, in which R³³ is hydrogen or C1-4 alkyl;

9) —S—CH₂—;

10) —CH₂—S—,

11) —SO₂NR³⁴—, in which R³⁴ is hydrogen or C1-4 alkyl;

12) —NR³⁵SO₂—, in which R³⁵ is hydrogen or C1-4 alkyl; non-toxic saltsthereof, or hydrates thereof,

(2) the blood coagulation factor VIIa inhibitors containing the compoundof formula (I) as active ingredient,

(3) processes for the preparation of the compound of formula (I).

DETAILED DESCRIPTION OF INVENTION

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkoxy and alkylene include straight andbranched isomers. Isomers based on double bond, ring, fused ring (E, Z,cis, trans), isomers resulting from the presence of asymmetric carbon(s)(R-configuration, S-configuration, α-configuration, β-configuration,enantiomers, diastereoisomers), optically active compound having opticalrotation (D, L, d, l-configuration), polar compounds obtained bychromatographic separations (high polar compound, low polar compound),equilibrium compounds, the mixtures are existed by free ratio, racemicmixtures are included in the present invention.

In the compound of the formula (I),

C1-4 alkyl represented by R³, R¹², R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³,R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸,

C1-4 alkyl in —COO—(C1-4 alkyl)-phenyl represented by R¹, R², R²⁴, R²⁶,

C1-4 alkyl in —O—(C1-4 alkyl)-phenyl represented by R³, R¹³,

C1-4 alkyl in —(C1-4 alkyl)-phenyl represented by R⁸, R⁹, R¹⁰, R¹¹, R¹⁴,R¹⁷, R²⁷, R²⁸, R²⁹,

C1-4 alkyl in —(C14 alkyl)—O—(C1-4 alkyl) represented by R⁸, R⁹, R¹⁰,R¹¹, R¹⁷,

C1-4 alkyl in —(C1-4 alkyl)—COOR⁹ represented by R⁴, R⁵,

C1-4 alkyl in —O—(C1-4 alkyl)—COOR¹¹ represented by R⁴, R⁵,

C1-4 alkyl in —(C1-4 alkyl)—O—(C1-4 alkyl)-phenyl represented by R⁶, R⁷,

C1-4 alkyl in —(C1-4 alkyl)—OH represented by R¹⁷, R²⁸, R²⁹,

C1-4 alkyl in —(C1-4 alkyl)—O—(C1-4 alkyl)—O—(C1-4 alkyl) represented byR¹⁷,

C1-4 alkyl in —(C1-4 alkyl)—NR²²—represented by J¹,

C1-4 alkyl in —(C1-4 alkyl)—NR²³CO— represented by J¹,

C1-4 alkyl in —S(O)_(r)—(C1-4 alkyl) represented in J²,

C1-4 alkyl in J²,

C1-4 alkyl in —(C1-4 alkyl)—R²⁴ represented in J²,

C1-4 alkyl in —imino(C1-4 alkyl) represented in J² and by R²⁶,

C1-4 alkyl in —(C1-4 alkyl)—OR¹⁷ represented by R⁶, R⁷,

C1-4 alkyl in —(C1-4 alkyl)—NR²⁵, R²⁶ represented by R²⁸, R²⁹ is methyl,ethyl, propyl, butyl and isomeric groups thereof.

C1-8 alkyl represented by R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁵, R¹⁶, J², C1-8alkyl as substituents of heterocyclic ring containing nitrogen atom andtetrazol ring represented by R⁴, R⁵ is methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl and isomeric groups thereof.

C1-4 alkoxy in C1-4 alkoxycarbonyl represented by R¹, R², C1-4 alkoxy inC1-4 alkoxycarbonyloxy represented by R¹, R², C1-4 alkoxy in C1-4alkoxycarbonyl as substituents of 5-7 membered saturated hetercyclicring represented by J² is methoxy, ethoxy, propoxy, butoxy and isomericgroups thereof.

C2-4 alkenyl in C2-4 alkenyloxycarbonyl represented by R¹, R², C2-4alkenyl in —(C2-4 alkenyl)—COOR¹⁰ represented by R⁴, R⁵ is ethenyl,propenyl, butenyl and isomeric groups thereof.

Halogen atom represented by R⁶, R⁷ is fluorine, chlorine, bromine oriodine.

Trihalomethyl in J² is methyl substituted by 3 of halogen atoms that isfluorine, chlorine, bromine or iodine.

C3-7 cycloalkyl as substituents in J² is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

C5-7 cycloalkyl as substituents in J² is cyclopentyl, cyclohexyl orcycloheptyl.

C2-5 acyl represented by R¹⁷, R²⁴ is acetyl, propionyl, butyryl, valeryland isomeric groups thereof.

5-7 membered unsaturated carbocyclic ring represented by E¹, E², E³ iscyclopentadiene, benzene, cycloheptatriene, etc. 5-7 membered saturatedcarbocyclic ring represented by E³ is cyclopentadane, cyclohexane,cycloheptane. 5-6 membered unsaturated carbocyclic ring represented byE⁴, and 5-6 membered unsaturated carbocyclic ring formed by two R⁶ iscyclopentadiene, benzene.

5-7 membered unsaturated or saturated heterocyclic ring represented byE¹, E², E³, 5-7 membered saturated heterocyclic ring in J², means 5-7membered unsaturated or saturated heterocyclic ring containing 1-2 ofhetero atom(s) selected by oxygen, sulfur and/or nitrogen.

For example, 5-7 membered unsaturated or saturated heterocyclic ringcontaining 1-2 of hetero atom(s) selected by oxygen, sulfur and/ornitrogen is piperidine, piperazine, tetrahydropyrimidine,hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine,hexahydroazepine, dihydrofuran, tetrahydrofuran, dihydropyran,tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain(dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran),dihydrooxazole, tetrahydrooxazole, dihydroisoxazole,tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole,dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine,pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine,thiophene, thiain (thiopyran), thiepin, oxazole, isoxazole, thiazole,isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine,thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine.

5-6 membered unsaturated heterocyclic ring represented by E⁴ means 5-6membered saturated heterocyclic ring containing one of oxygen, sulfur ornitrogen, for example, furan, thiophene, pyrrole, pyridine.

5-6 membered saturated heterocyclic ring represented by J² means 5-6membered saturated heterocyclic ring containing 1-2 of hetero atom(s)selected by oxygen atom, sulfur atom and/or nitrogen atom, for example,oxolane, oxane, pyrrolidine, piperidiene, dioxolane, dioxane,imidazolidine, pyrazolidine, piperazine, morpholine.

A saturated heterocyclic ring containing nitrogen formed by R¹⁸ and J²taken together with the nitrogen atom to which they are attached, or R²⁸and R²⁹ taken together with the nitrogen atom to which they are attachedmeans 5-6 membered saturated heterocyclic ring containing one nitrogen,two nitrogens, one nitrogen and one oxygen, or one nitrogen and onesulfur, for example, pyrrolidine, piperidine, imidazolidine,pyrazolidine, piperazine, morpholine, thiomorpholine.

5-6 membered saturated heterocyclic ring formed by two R⁶ taken togetherwith the neighboring two carbon of E⁴ ring to which they are attachedmeans 5-6 membered saturated heterocyclic ring containing 1-2 of heteroatom(s) of oxygen, sulfur and/or nitrogen, for example, oxolane, oxane,pyrrolidine, piperidiene, thiolane, thiane, dioxolane, dioxane,imidazolidine, pyrazolidine, dithiolane, dithiane, piperazine,oxathiane, morpholine, thiomorpholine.

In the formula (I), the ring represented by

means E³ ring is absent, that is only E² ring represents ring, and bothof E² ring and E³ ring represent ring, for example, benzene,naphthalene, 1,2,3,4-tetrahydronaphthalene, indan, benzofuran,2,3-dihydrobenzofuran, benzoimidazole, 1,3-dioxaindan, benzothiophene,pyridine, pyrimidine, isoquinoline, thiophene, furan. Especiallypreferable group is benzene, pyridine, thiophene, furan.

In the formula (I), as ring represented by

benzene, naphthalene, 2,3-dihydrobenzofuran, 1,3-dioxaindan, pyridine,furan, thiophen are preferable. Especially preferable group is benzene,pyridien, furan, thiophene.

In the formula (I), all groups represented by R⁴ and R⁵ are preferable.Especially preferable group is COOR⁸.

Besides, especially preferable attachment point on E⁴ ring of one R⁴ isortho position.

In the formula (I), all groups represented by R⁶ are preferable.Especially preferably, at least one of R⁶ is —J¹—J².

In the formula (I), all groups represented by R⁷ are preferred.Especially preferably, at least one of R⁷ is hydrogen, C1-4 alkyl,nitro, NR¹⁵R¹⁶, OR¹⁷, —(C1-4 alkyl)—OR¹⁷.

In the formula (I), all groups represented by A are preferable.Especially preferable groups are —CH₂—O—, NR³⁰CO—, —NR³¹CHR³²—.

In the compound of the formula (I), the compound of the formula

and the compound of the formula

are equivalence, and the compound of the formula

and the compound of the formula

are equivalence.

In the compounds of the present invention of formulae (I), the compoundsof the formula (I-1):

wherein A^(a) is —CH₂—O—, —N³⁰CO— in which R³⁰ is as hereinbeforedefined; —NR³¹CHR³²— in which R³¹ and R³² are as hereinbefore defined;pp and qq each independently, is 0-1, with the proviso that pp+qq is 0or 1, the other symbols are as hereinbefore defined, with the provisiothat A^(a) and E⁴ ring attach to E² ring at ortho position, E² ring andessential one R⁴ attach to E⁴ ring at ortho position; are preferable.

The following compounds of the formulae are especially preferable: theformula (Ia):

wherein all the symbols are as hereinbefore defined;

the formula (Ib):

wherein all the symbols are as hereinbefore defined;

the formula (Ic):

 wherein all the symbols are as hereinbefore defined;

the formula (Id):

 wherein all the symbols are as hereinbefore defined;

the formula (Ie):

 wherein all the symbols are as hereinbefore defined;

the formula (If):

 wherein all the symbols are as hereinbefore defined;

the formula (Ig):

 wherein all the symbols are as hereinbefore defined;

the formula (Ih):

 wherein all the symbols are as hereinbefore defined;

the formula (Ii):

 wherein all the symbols are as hereinbefore defined;

non-toxic salts thereof, or hydrates thereof.

As the specific compounds described in Table 1-Table 27, non-toxic saltsthereof and hydrates thereof, and the compounds described in theExamples are preferable.

The following compounds include isomers resulting from the presence ofasymmetric carbon(s), that is R-configuration, S-configuration andRS-configuration are also included.

TABLE 1 (Ia-1)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 2 (Ia-2)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 3 (Ia-3)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 4 (Ib-1)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 5 (Ib-2)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 6 (Ib-3)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 7 (Ic-1)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 8 (Ic-2)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 9 (Ic-3)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 10 (Id-1)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 11 (Id-2)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 12 (Id-3)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 13 (Ie-1)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 14 (Ie-2)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 15 (Ie-3)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 16 (If-1)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 17 (If-2)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 18 (If-3)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 19 (Ig-1)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 20 (Ig-2)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 21 (Ig-3)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 22 (Ih-1)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 23 (Ih-2)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 24 (Ih-3)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 25 (Ii-1)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 26 (Ii-2)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

TABLE 27 (Ii-3)

No. R⁷ R⁶⁶  1 H

 2 H

 3 H

 4 H

 5 H

 6 H

 7 CH₃

 8 CH₃

 9 CH₃

10 CH₃

11 CH₃

12 CH₃

13 OCH₃

14 OCH₃

15 OCH₃

16 OCH₃

17 OCH₃

18 OCH₃

Salts

Non-toxic salts of the present invention include all pharmaceuticallyacceptable salts.

The compounds of formulae (I) of the present invention may be convertedinto the corresponding salts. Non-toxic salts and water-soluble saltsare preferred. Suitable salts, for example, include: salts of alkalimetals (e.g. potassium, sodium), salts of alkaline earth metals (e.g.calcium, magnesium), ammonium salts, salts of pharmaceuticallyacceptable organic amines (e.g. tetramethylammonium, triethylamine,methylamine, dimethylamine, cyclopentylamine, dicyclohexylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)amine, lysine, arginine,N-methyl-D-glucamine).

The compounds of formulae (I) may be converted into the correspondingacid addition salts. Non-toxic acid addition salts and water-solubleacid addition salts are preferred. Suitable salts, for example, include:salts of inorganic acids e.g. hydrochloride, hydrobromide, sulfate,phosphate, nitrate; salts of organic acids e.g. acetate,trifluoroacetate, lactate, tartarate, oxalate, fumarate, maleate,citrate, benzoate, methanesulphonate, ethanesulphonate,benzenesulphonate, toluenesulphonate, isethionate, glucuronate,gluconate.

The compounds of formulae (I) and salts thereof may be converted intothe corresponding hydrates by conventional manner.

Process for the Preparation of the Present Compound

(a-1) In the compound of the present invention of the formula (I), thecompound in which A is —NR³⁰CO—, and R¹, R² and R³ are not groupsincluding hydroxy, and R⁴ and R⁵ are groups excepting CONR¹²R¹³ and arenot groups including —COOH, P(O)(OH)₂ and tetrazol-5-yl, and R⁶ and R⁷are not groups including amino and are optionally protected hydroxy, E⁴ring is not pyrrole, furan and thiophene, that is the compound of theformula (I-A-1):

wherein

R¹⁻¹, R²⁻¹ and R³⁻¹ each independently, is a same meaning as R¹, R² andR³, with the proviso that in the case of R¹, R² and R³ are groupsincluding hydroxy, then the hydroxy represented by corresponding R¹⁻¹,R²⁻¹ and R³⁻¹ is protected hydroxy,

R⁴⁻¹ is a same meaning as R⁴ excepting CONR¹²R¹³, with the proviso thatin the case of R⁴ is groups including —COOH, P(O)(OH)₂ and tetrazol-5yl,then —COOH, P(O)(OH)₂ and tetrazol-5yl represented by corresponding R⁴⁻¹are protected —COOH, P(O)(OH)₂ and tetrazol-5yl,

R⁵⁻¹ is a same meaning as R⁵ excepting CONR¹²R¹³, with the proviso thatin the case of R⁵ is groups including —COOH, P(O)(OH)₂ and tetrazol-5yl,then —COOH, P(O)(OH)₂ and tetrazol-5yl represented by corresponding R⁵⁻¹are protected —COOH, P(O)(OH)₂ and tetrazol-5yl,

R⁶⁻¹ and R⁷⁻¹ are a same meaning as R⁶ and R⁷, with the proviso that inthe case of R⁶ and R⁷ are groups including hydroxy and amino, then thehydroxy and amino represented by corresponding R⁶⁻¹ and R⁷⁻¹ are hydroxyor protected hydroxy and protected amino,

A¹ is —NR³⁰CHO—,

E^(4a) ring is a same meaning as E⁴, with the proviso that it is notpyrrole, furan and thiophene, the other symbols are as hereinbeforedefined;

may be prepared by amidation the compound of the formula (II):

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (III):

wherein all the symbols are as hereinbefore defined;

or in the case of the compound in which R⁶⁻¹ and R⁷⁻¹ are the groupcontaining protected hydroxy, continually, may be prepared bydeprotection.

The method of amidation is known. It includes the method

(1) via an acyl halide,

(2) via a mixed acid anhydride,

(3) using a condensing agent.

These methods are explained as follows.

(1) The method via an acyl halide, for example, may be carried out in anorganic solvent (e.g. chloroform, methylene chloride, diethyl ether ortetrahydrofuran, ethyl acetate) or without a solvent, using an acylhalide (e.g. oxalyl chloride or thionyl chloride) at −20° C. to refluxtemperature, and the obtained acyl halide derivative may be reacted withan amine in an organic solvent (e.g. chloroform, methylene chloride,diethyl ether or tetrahydrofuran) in the presence of a tertiary amine(e.g. pyridine, triethyl amine, dimethyl aniline ordimethylaminopyridine) at 0-40° C.

(2) The method via a mixed acid anhydride may be carried out, forexample, by reacting a carboxylic acid with an acyl halide (e.g.pivaloyl chloride, tosyl chloride, mesyl chloride, ethyl chloroformateor isobutyl chloroformate) in an organic solvent (e.g. chloroform,methylene chloride, diethyl ether or tetrahydrofuran) or without asolvent, in the presence of a tertiary amine (e.g. pyridine,triethylamine, dimethylaniline or dimethylaminopyridine,N-methylmorpholine) at −20° C.-40° C., and the obtained mixed acidanhydride derivative may be reacted with a corresponding amine in anorganic solvent (e.g. chloroform, methylene chloride, diethyl ether ortetrahydrofuran) at 0-40° C.

(3) The method using a condensing agent (e.g. 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide(EDC) or 2-chloro-1-methylpyridinium iodide, 1,1′-carbonyldiimidazole(CDI)) may be carried out, for example, by reacting a carboxylic acidwith an amine in an organic solvent (e.g. chloroform, methylenechloride, dimethylformamide, diethyl ether, tetrahydrofuran) or withouta solvent, optionally in the presence of a tertiary amine (e.g.pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) usinga condensing agent, using 1-hydroxybenzotriazole (HoBt) or without HoBtat 0-40° C.

The reaction described in (1), (2) and (3) may be carried out under aninert gas (e.g. argon, nitrogen) to avoid water in order to obtain apreferable result.

The deprotection of hydroxy is known, for example, it includes themethod deprotection under acidic conditions or hydrogenolysis.

Deprotection under acidic conditions, for example, may be carried out ina solvent (e.g. methylene chloride, chloroform, dioxane, ethyl acetate,anisole) or without solvent, using an organic acid (e.g. acetic acid,trifluoroacetic acid, methansulfonic acid, trimethylsilyl iodide), or aninorganic acid (e.g. hydrogen chloride) or a mixture thereof (e.g.hydrogen bromide acetic acid) at 0-90°C.

Hydrogenolysis, for example, may be carried out in a solvent (e.g.tetrahydrofuran, dioxane, diethyl ether, ethyl acetate, methanol,ethanol), in the presence of a catalyst (e.g. palladium on carbon,palladium, palladium hydroxide, palladium acetate, palladium black,platinum black, nickel or Raney-nickel), at ordinary or elevatedpressure of hydrogen gas at 0-80° C.

(a-2) In the compound of the present invention of the formula (I), thecompound in which A is —NR³⁰CHO—, and R¹, R² and R³ are not groupsincluding hydroxy, and R⁴ and R⁵ are groups excepting CONR¹²R¹³ and arenot groups including —COOH, P(O)(OH)₂ and tetrazol-5-yl, and R⁶ and R⁷are not groups including hydroxy and amino, E⁴ ring is pyrrole, furan orthiophene, that is the compound of the formula (I-A-2):

wherein

E^(4b) is pyrrole, furan or thiophene,

R⁶⁻² and R⁷⁻² are a same meaning as R⁶ and R⁷, with the proviso that inthe case of R⁶ and R⁷ are groups including hydroxy and amino, then thehydroxy and amino represented by corresponding R⁶⁻² and R⁷⁻² areprotected hydroxy and protected amino, the other symbols are ashereinbefore defined;

may be prepared by subjecting to condensation reaction, the compound ofthe formula (XI-a):

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (IX):

H₂N—R¹  (IX)

wherein R¹ is as hereinbefore defined.

The condensation reaction is known, for example, it may be carried outby reacting with the compound of the formula (IX) or salt thereof inorganic solvent (e.g. methanol, ethanol, acetonitrile, methylenechloride, diethyl ether, tetrahydrofuran, toluene, dimethylformamide)without a solvent, optionally in the presence of an base (e.g.triethylamine, sodium hydride, sodium methoxide, sodium ethoxide) at 0°C. to reflux temperature.

(b) In the compound of the present invention of the formula (I), thecompound in which A is —SO₂NR³⁴— or —NR³⁵SO₂—, and R¹, R² and R³ are notgroups including hydroxy, and R⁴ and R⁵ are groups excepting CONR¹²R¹³and are not groups including —COOH, P(O)(OH)₂ and tetrazol-5-yl, and R⁶and R⁷ are not groups including amino and optionally protected hydroxy,that is the compound of the formula (I-B):

wherein A² is —SO₂NR³⁴— or —NR³⁵SO₂—, the other symbols are ashereinbefore defined;

may be prepared by reacting the compound of the formula (IV-1):

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (V-1):

wherein all the symbols are as hereinbefore defined;

or by reacting the compound of the formula (IV-2):

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (V-2):

wherein all the symbols are as hereinbefore defined;

or in the case of the compound in which R⁶⁻¹ and R⁷⁻¹ are the groupcontaining protected hydroxy, continually, may be prepared bydeprotection.

The above reaction is known, for example, may be carried out by reactingsulfonic acid and acyl halide (e.g. oxalyl chloride or thionyl chloride)in an organic solvent (e.g. chloroform, methylene chloride, diethylether, tetrahydrofuran, ethyl acetate) or without a solvent at −20° C.to reflux temperature, and the obtained acyl halide derivative may bereacted with an amine in an organic solvent (e.g. chloroform, methylenechloride, diethyl ether or tetrahydrofuran) in the presence of atertiary amine (e.g. pyridine, triethyl amine, dimethyl aniline ordimethylaminopyridine) at 0-40° C.

The deprotection reaction is known, for example, may be carried out asmethod hereinbefore defined.

(c-1) In the compound of the present invention of the formula (I), thecompound in which A is —O—CH₂—, —S—CH₂—, —NR³¹CHR³²⁻¹—, and R¹, R² andR³ are not groups including hydroxy, and R⁴ and R⁵ are groups exceptingCONR¹²R¹³ and are not groups including —COOH, P(O)(OH)₂ andtetrazol-5-yl, and R⁶ and R⁷ are not groups including hydroxy and amino,E⁴ ring is not pyrrole, furan and thiophene, that is the compound of theformula (I-C-1):

wherein

A³ is —O—CH₂—, —S—CH₂— or —NR³¹CHR³²⁻¹—, in which

R³²⁻¹ is hydrogen, cyano, COO³⁶⁻¹, in which

R³⁶⁻¹ is C1-4 alkyl; or CONR³⁷⁻¹R³⁸⁻¹, in which

R³⁷⁻¹ and R³⁸⁻¹ each independently, is hydrogen, C1-4 alkyl, but bothare not hydrogen at the same time; the other symbols are as hereinbeforedefined;

may be prepared by alkylation the compound of the formula (VI):

wherein

R³⁹ is halogen atom, methansulfonyloxy or p-toluenesulfonyloxy, theother symbols are as hereinbefore defined;

with the compound of the formula (VII):

wherein

R⁴⁰ is —OHSH or —NHR³¹, the other symbols are as hereinbefore defined.

The above alkylation is known, for example, may be carried out in aninert organic solvent (e.g. tetrahydrofuran (THF), diethyl ether,methylene chloride, chloroform, carbon tetrachloride, pentane, hexane,benzene, toluene, dimethylformamide (DMF), dimethylsulfoxide (DMSO),hexamethylphosphric triamide (HMPA)), in the presence of an base (e.g.sodium hydride, potassium carbonate, triethylamine, pyridine, sodiumiodide, cesium carbonate) at 0-80° C.

In the case of the compound in which A³ or —NR³¹CH₂—, it may be alsoprepared by subjecting the compound of the formula (XII):

wherein all the symbols are as hereinbefore defined;

to pinner method.

The pinner method is known, for example, it may be carried out in anorganic solvent (e.g. ethanol, methylene chloride) using hydrochlorideat 0-50° C., continually, in an organic solvent (e.g. methanol, ethanol)using ammonium gas at 0-50° C.

(c-2) In the compound of the present invention of the formula (I), thecompound in which A is —O—CH₂—, —S—CH₂— or —NR³¹CHR³²⁻¹, and R¹, R² andR³ are not groups including hydroxy, and R⁴ and R⁵ are groups exceptingCONR¹²R¹³ and are not groups including —COOH, P(O)(OH)₂ andtetrazol-5-yl, and R⁶ and R⁷ are not groups including hydroxy and amino,E⁴ ring is pyrrole, furan or thiophene, that is the compound of theformula (I-C-2):

wherein

A³ is —O—CH₂—, —S—CH₂— or —NR³¹CHR³²⁻¹—, the other symbols are ashereinbefore defined;

may be prepared by subjecting to condensation reaction, the compound ofthe formula (XI-b):

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (IX):

H₂N—R¹  (IX)

wherein R¹ is as hereinbefore defined.

The condensation reaction is known, for example, it may be carried outas method hereinbefore defined.

(d-1) In the compound of the present invention of the formula (I), thecompound in which A is vinylene, ethynylene, —CH₂—O—, —CH₂—NR³³—,—CH₂—S—, and R³ are not groups including hydroxy, and R⁴ and R⁵ aregroups excepting CONR¹²R¹³ and are not groups including —COOH, P(O)(OH)₂and tetrazol-5-yl, and R⁶ and R⁷ are not groups including hydroxy andamino, when A is vinylene or ethynylene, then E⁴ ring is not pyrrole,furan and thiophene, that is the compound of the formula (I-D-1):

wherein

A⁴ is vinylene, ethynylene, —CH₂—O—, —CH₂—NR³³—, —CH₂—S—,

E^(4c) ring is a same meaning as E⁴ ring, with the proviso that it isnot pyrrole, furan and thiophene, when A is vinylene or ethynylene, theother symbols are as hereinbefore defined;

may be prepared by subjecting to condensation reaction, the compound ofthe formula (VIII):

wherein

R⁴¹ is —O— or —S—, and the other symbols are as hereinbefore defined;

with the compound of the formula (IX):

H₂N—R¹  (IX)

 wherein R¹ is as hereinbefore defined.

The above reaction is known, for example, the compound of the formula(VIII) may be carried out by reacting with the compound of the formula(IX) or salts thereof in an organic solvent (e.g. methanol, ethanol,acetonitrile, methylene chloride, diethyl ether, tetrahydrofuran,toluene, dimethylformamide) or without a solvent, optionally in thepresence of an base (e.g. triethylamine, sodium hydride, sodiummethoxide, sodium ethoxide) at 0° C. to reflux temperature.

(d-2) In the compound of the present invention of the formula (I), thecompound in which A is vinylene, ethynylene, and R³ are not groupsincluding hydroxy, and R⁴ and R⁵ are groups excepting CONR¹²R¹³ and arenot groups including —COOH, P(O)(OH)₂ and tetrazol-5-yl, and R⁶ and R⁷are not groups including hydroxy and amino, E⁴ ring is pyrrole, furan orthiophene, that is the compound of the formula (I-D-2):

wherein

A⁴⁻² is vinylene, ethynylene, and the other symbols are as hereinbeforedefined;

may be prepared by subjecting to condensation reaction, the compound ofthe formula (XI-c):

wherein all the symbols are as hereinbefore defined;

with the compound of the formula (IX):

H₂N—R¹  (IX)

wherein R¹ is as hereinbefore defined.

The condensation reaction is known, for example, it may be carried outas method hereinbefore defined.

(e) In the compound of the present invention of the formula (I), thecompound in which A is ethylene, and R¹, R² and R³ are not groupsincluding hydroxy; and R⁴ and R⁵ are groups excepting CONR¹²R¹³ and arenot groups including —COOH, P(O)(OH)₂ and tetrazol-5-yl, and R⁶ and R⁷are not groups including hydroxy and amino, that is the compound of theformula (I-E):

wherein

A⁵ is ethylene, and the other symbols are as hereinbefore defined;

may be prepared by subjecting to reduction the compound in which A⁴ isvinylene or ethynylene in the compound of the formula (I-D-1), or thecompound of the formula (I-D-2).

The above reduction reaction is known, for example, in an organicsolvent (e.g. tetrahydrofuran, dioxane, diethyl ether, ethyl acetate,methanol, ethanol), using a catalyst (e.g. palladium on carbon,palladium, palladium hydroxide, palladium acetate, palladium black,platinum black, nickel or Raney-nickel), at ordinary or elevatedpressure of hydrogen gas at 0-80° C.

(f) In the compound of the present invention of the formula (I), R⁴ andR⁵ are groups excepting CONR¹²R¹³, R¹, R² and R³ are groups includinghydroxy, or R⁴ and R⁵ are groups including —COOH, P(O)(OH)₂ andtetrazol-5-yl, or R⁶ and R⁷ are groups including hydroxy and amino, thatis the compound of the formula (I-F):

wherein

R¹⁻², R²⁻², R³⁻², R⁶⁻³ and R⁷⁻³ each is the same meaning as R¹, R², R³,R⁶ and R⁷, R⁴⁻² and R⁵⁻² each is the same meaning as R⁴ and R⁵ exceptingCONR¹²R¹³, with the proviso that at least one of R¹⁻², R²⁻², R³⁻², R⁴⁻²,R⁵⁻², R⁶⁻³, and R⁷⁻³ is hydroxy, —COOH, amino, P(O)(OH)₂, tetrazol-5-yl,or a group including them, the other symbols are as hereinbeforedefined;

may be prepared by deprotection under an alkaline condition,deprotection under an acidic conditions and/or hydrogenolysis, thecompound of the formula (I-A-1), (I-A-2), (I-B),(I-C-1), (I-C-2),(I-D-1), (I-D-2) or (I-E).

Deprotection under an alkaline condition is known, for example, may becarried out in an organic solvent (e.g. methanol, tetrahydrofuran,dioxane), using an alkali metal hydroxide (e.g. sodium hydroxide,potassium hydroxide, lithium hydroxide), an alkaline earth metalhydroxide (e.g. calcium hydroxide) or a carbonate (e.g. sodiumcarbonate, potassium carbonate), or an aqueous solution thereof ormixture thereof at 0-40° C.

Deprotection under acidic conditions, for example, may be carried out ina solvent (e.g. methylene chloride, chloroform, dioxane, ethyl acetate,anisole) or without a solvent, using an organic acid (e.g. acetic acid,trifluoroacetic acid, methansulfonic acid, trimethylsilyl iodide), or aninorganic acid (e.g. hydrogen chloride) or a mixture thereof (e.g.hydrogen bromide acetic acid) at 0-90° C.

Hydrogenolysis, for example, may be carried out in a solvent (e.g.tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol), in thepresence of a catalyst (e.g. palladium on carbon, palladium, palladiumhydroxide, palladium acetate, palladium black, platinum black, nickel orRaney-nickel), at ordinary or elevated pressure of hydrogen gas at 0-80°C.

(g) In the compound of the present invention of the formula (I), R⁴ andR⁵ are CONR¹²R¹³, that is the compound of the formula (I-G):

wherein

R⁴⁻³ and R⁵⁻³ each independently, is CONR¹²R¹³, and R¹⁻², R²⁻², R³⁻²,R⁶⁻³ and R⁷⁻³ each is the same meaning as R¹, R², R³, R⁶ and R⁷, withthe proviso that at least one of R¹⁻², R²⁻², R³⁻², R⁶⁻³ and R⁷⁻³ ishydroxy, —COOH, amino or a group including them, the other symbols areas hereinbefore defined;

may be prepared by amidation the compound in which at least one of R⁴and R⁵ is —COOH or a group including it in the compound of the formula(I-F), with the compound of the formula (X):

NHR¹²R¹³  (X)

wherein all the symbols are as hereinbefore defined.

Amidation is known, for example, it may be carried out by the samemethod as hereinbefore described.

As will be apparent to those skilled in the art, t-butyl or benzyl maybe used as protecting groups for carboxyl, and t-butyl, benzyl,t-butyldimethylsilyl, trimethylsilyl may be used as protecting groupsfor hydroxy, but other groups which may be removed easily andselectively are also preferred. For example, the groups described in T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York,1991, may be used.

Benzyloxycarbonyl, t-butoxycarbonyl may be used as protecting groups foramino, but other groups which may be removed easily and selectively arealso preferred.

t-Butyl or benzyl may be used as protecting groups for hydroxylamine,but other groups which may be removed easily and selectively are alsopreferred. For example —C(CH₃)₂—OCH₃ may be used.

The desired compound of the present invention may be easily preparedusing these protecting groups.

The compound of the formula (II), (III), (IV-1), (IV-2), (V-1), (V-2),(VI), (VII), (VIII), (IX), (X), (XI-a), (XI-b), (XI-c) and (XII) areknown per se or may be prepared by known methods, or methods in theExamples.

For example, the compound of the formula (II), (V-1), (V-2), (VI),(VIII), (XI), and (XII) may be prepared by using a reaction depicted infollowing schemes.

Symbols in each schemes mean as follows, the other symbols are ashereinbefore defined.

L: OTf, halogen atom,

Tf: trifluoromethansulfonyl,

M: —B(OH)₂, —Sn(C1-4 alkyl)₃,

R⁴²: a general protecting groups of amine,

R⁴³: a general protecting groups of hydroxy,

Tf₂O: trifluoromethansulfonic acid anhydrous,

HC(SMe)₃: tris(methylthio)methane,

NBS: N-bromosuccinimide,

TMSCN: trimethylsilylcyanide,

HClaq: an aqueous solution of hydrochloric acid,

MsCl: methanesulfonyl chloride,

TsCl: p-toluenesulfonyl chloride,

A⁴⁻¹: —CH₂—O—, —CH₂—NR³³—, —CH₂—S—,

A⁶: —NR³⁰CO—, —O—CH₂—, —S—CH₂—, —NR³¹CHR³²⁻¹—, vinylene, ethylene,

NaSH: sodium bisulfate,

Mel: methyl iodide,

MeOH: methanol.

The starting materials in each scheme are known per se or may beprepared by known methods.

The reaction in each scheme are carried out by known methods.

The other starting materials and reagents in the present invention areknown per se or may be prepared by known methods.

Pharmacological Activities

(1) FVIIa inhibitory activity

10 μl of the compound of the present invention in 10% DMSO were added to65 μl of the buffer solution including FVIIa (ADI#407, final 10 nM),tissue factor (ADI#4500, final 10 nM) and calcium chloride. The mixturewas incubated for 10 minutes at 37° C., then 25 μl of 2 mMH-D-Ile-Pro-Arg-pNA (Chromogenix S-2288) was added (total volume 100μl). The absorbance was measured at 405 nm at regular time intervals,and an initial velocity was calculated. The control value was measuredwith 10% of DMSO. Inhibitory activity was expressed as a 50% inhibitionof control (IC50).

The final concentration of calcium chloride and S-2288 were 2 mM and 0.5mM respectively. The buffer solution consisted of 50 mMtris-hydrochloric acid buffer (pH 7.5) containing 0.2% PEG6000 and 150mM sodium chloride.

These results are shown in Table 28.

TABLE 28 Compound IC50 (μM) Example 19(47) 0.012 Example 46 0.013

(2) Anticoagulant effect on the prothrombin time (PT) and the activatedpartial thromboplastin time (APTT)

PT is assayed by addition of tissue factor and indicates the coagulantactivity of the extrinsic pathway, and APTT is assayed by addition ofnegative charged substances and indicates the coagulant activity of theintrinsic pathway.

The assay method was as follows.

Purified human plasma (verify reference plasma, organon technica) andthe compound of the present invention in 10% DMSO solution were mixed atthe rate of 9:1.

(a) PT determination

An automatic coagulation determination device (Sysmex CA5000) was usedfor the measurement of blood coagulation time, using the plasmadescribed above and thromboplastin C (Dade).

The control value was determined by adding solvent without the compoundof the present invention. The concentration of the compound of thepresent invention at which the coagulation time prolonged two time ofthe control (PTCT2), was calculated.

(b) APTT determination

An automatic coagulation determination device (Sysmex CA5000) was usedfor the measurement of blood coagulation time, using the plasmadescribed above, datefy APTT (Dade) and 20 mM calcium chloride.

The control value was determined by adding solvent without the compoundof the present invention. The concentration of the compound of thepresent invention at which the coagulation time prolonged two time ofthe control (APTTCT2), was calculated, and an extension rate (%) of APTTon PTCT2 were estimated.

An extension rate of APTT on PTCT2 of the compound of the presentinvention was not effective.

INDUSTRIAL APPLICABILITY

Toxicity

The toxicity of the compounds of the present invention is very low andtherefore the compounds may be considered safe for pharmaceutical use.

Utility

The formula (I) of amidino derivatives, their non-toxic salts andhydrates have an inhibitory activity for a blood coagulation factor VIIaand are useful for treatment and/or prevention of severalangiopathologic diseases due to the hypercoagulability, such asdisseminated intravascular coagulation, coronary thrombosis (e.g. acutemyocardial infarction, unstable angina), cerebral infarction, cerebralembolism, transient ischemic attack, diseases caused by cerebrovasculardisorders, pulmonary vascular diseases (e.g. pulmonary infarction,pulmonary embolism), deep venous thrombosis, peripheral arterialobstruction, thrombosis after artificial vascular transplantation andartificial valve transplantation, post-operative thrombosis,reobstruction and restenosis after coronary artery bypass operation,reobstruction and restenosis after PTCA (percutaneous transluminalcoronary angioplasty) or PTCR (percutaneous transluminal coronaryrecanalization), thrombosis by extracorporeal circulation andprocoagulative diseases such as glomerlonephriitis.

Application for Pharmaceuticals

For the purpose above described, the compounds of formulae (I) of thepresent invention, non-toxic salts, acid addition salts or hydratesthereof may be normally administered systemically or locally, usually byoral or parenteral administration.

The doses to be administered are determined depending upon, for example,age, body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment. In the human adult,the doses per person are generally from 1 mg to 1000 mg, by oraladministration, up to several times per day, and from 0.1 mg to 100 mg,by parenteral administration (preferably intravenous administration), upto several times per day, or continuous administration from 1 to 24hours per day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

The compounds of the present invention may be administered in the formof, for example, solid forms for oral administration, liquid forms fororal administration, injections, liniments or suppositories forparenteral administration.

Solid forms for oral administration include compressed tablets, pills,capsules, dispersible powders, and granules. Capsules include hardcapsules and soft capsules.

In such solid forms, one or more of the active compound(s) may beadmixed with vehicles (such as lactose, mannitol, glucose,microcrystalline cellulose, starch), binders (such as hydroxypropylcellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate),disintegrants (such as cellulose calcium glycolate), lubricants (such asmagnesium stearate), stabilizing agents, and solution adjuvants (such asglutamic acid or aspartic acid) and prepared according to methods wellknown in normal pharmaceutical practice. The solid forms may, ifdesired, be coated with coating agents (such as sugar, gelatin,hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), orbe coated with two or more films. And further, coating may includecontainment within capsules of absorbable materials such as gelatin.

Liquid forms for oral administration include pharmaceutically acceptablesolutions, suspensions and emulsions, syrups and elixirs. In such forms,one or more of the active compound(s) may be dissolved, suspended oremulized into diluent(s) commonly used in the art (such as purifiedwater, ethanol or a mixture thereof. Besides such liquid forms may alsocomprise some additives, such as wetting agents, suspending agents,emulsifying agents, sweetening agents, flavoring agents, aroma,preservative or buffering agent.

Injections for parenteral administration include sterile aqueous,suspensions, emulsions and solid forms which are dissolved or suspendedinto solvent(s) for injection immediately before use. In injections, oneor more of the active compound(s) may be dissolved, suspended oremulized into solvent(s). The solvents may include distilled water forinjection, physiological salt solution, vegetable oil, propylene glycol,polyethylene glycol, alcohol, e.g. ethanol, or a mixture thereof.

Injections may comprise some additives, such as stabilizing agents,solution adjuvants (such as glutamic acid, aspartic acid orPOLYSORBATE80 (registered trade mark)), suspending agents, emulsifyingagents, soothing agent, buffering agents, preservative. They may besterilized at a final step, or may be prepared and compensated accordingto sterile methods. They may also be manufactured in the form of sterilesolid forms which may be dissolved in sterile water or some othersterile diluent(s) for injection immediately before use.

Other forms for parenteral administration include liquids for externaluse, ointments and endermic liniments, inhalations, sprays,suppositories and pessaries for vaginal administration which compriseone or more of the active compound(s) and may be prepared by methodsknown per se. Sprays may comprise additional substances other thandiluents, such as stabilizing agents (such as sodium sulfate), isotonicbuffers (such as sodium chloride, sodium citrate or citric acid). Forpreparation of such sprays, for example, the method described in theU.S. Pat. No. 2,868,691 or 3,095,355 may be used.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Reference Examples and Examples illustrate the presentinvention, but do not limit the present invention.

The solvents in the parentheses show the developing or eluting solventsand the ratios of the solvents used are by volume in chromatographicseparations or TLC.

The solvents in the parentheses in NMR show the solvents used inmeasurement.

REFERENCE EXAMPLE 1

Benzyl 2-trifluoromethylsulfonyloxy-5-formylbenzate

Potassium bicarbonate (3.3 g) and benzyl bromide (3.9 ml), successively,were added to a solution of 2-hydroxy-5-formylbenzoic acid (5 g) indimethylformamide (80 ml) under an atmosphere of argon at roomtemperature. The mixture was stirred for 14 hours at room temperature.The reaction mixture was poured into water (150 ml). The solution wasextracted with ethyl acetate. The extract was washed with a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated. To a solution of the residue (5.9 g) inmethylene chloride (25 ml), pyridine (9.3 ml) andtrifluoromethanesulfonic acid anhydrous (7.7 ml), successively, wereadded under an atmosphere of argon at 0° C. The mixture was stirred for30 minutes. The reaction mixture was poured into water (60 ml). Thesolution was extracted with ethyl acetate (150 ml). The extract waswashed with a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=5:1) togive the present compound (6.23 g) having the following physical data.

TLC: Rf 0.33 (Hexane:Ethyl acetate=5:1); NMR (CDCl₃): δ 10.1 (1H, s),8.57 (1H, d, J=2.2 Hz), 8.16 (1H, dd, J=2.2, 8.4 Hz), 7.52-7.38 (6H, m),5.45 (2H, s).

REFERENCE EXAMPLE 2

3-benzyloxycarbonyl-4-trifluoromethylsulfonyloxybenzoic acid

To the mixed solution of the compound prepared in Reference Example 1(1.86 g)in t-butanol—acetonitrile—water (27 ml; 6:1:2),2-methyl-2-butene (2.3 ml), sodium dihydrogenphosphate (690 mg) andsodium chloride (1.9 g), successively, were added. The mixture wasstirred for 20 minutes at room temperature. The reaction mixture waspoured into ice-water. The solution was extracted with ethyl acetate (60ml, 2 times). The extract was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous magnesium sulfate andconcentrated. The residue (1.94 g) was used to the next reaction withoutbeing purified.

TLC: Rf 0.23 (Chloroform:Methanol:Water=9:1:0.1).

REFERENCE EXAMPLE 3

Benzyl 2-trifluoromethylsulfonyloxy-5-((2,2-dimethylpropyl)carbamoyl)benzoate

Oxalyl chloride (0.21 ml) and dimethylformamide (1 drop) were added to asolution of the compound (808 mg) prepared in Reference Example 2 inmethylene chloride (8 ml) under an atmosphere of argon at 0° C. Themixture was stirred for 3 minutes at 0° C., and stirred for 1 hour atroom temperature. The reaction mixture was concentrated. The residue wasdistilled off an azeotropic mixture with toluene (5 ml, 2 times). Theresidue was dissolved into methylene chloride (8 ml), and cooled to 0°C. Triethylamine (0.5 ml) and 2,2-dimethylpropylamine (0.24 ml) wereadded to the solution. The mixture was stirred for 5 minutes at 0° C.,stirred for 10 minutes at room temperature. The reaction mixture waspoured into ice-water (30 ml). The solution was extracted with ethylacetate (30 ml, 2 times). The extract was washed with a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=5:1) to give thepresent compound (857 mg) having the following physical data. NMR(CDCl₃): δ 8.39 (1H, d, J=2.6 Hz), 8.08 (1H, dd, J=2.6, 8.4 Hz),7.50-7.37 (6H, m), 6.16 (1H, brs), 5.44 (2H, s), 3.28 (2H, d, J=6.4 Hz),0.98 (9H, s).

REFERENCE EXAMPLE 4

Benzyl 2′-formyl-4-((2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylate

2-formylphenylboric acid (269 mg) tripotassium phosphate (569 mg) addedto a solution of the compound prepared in Reference Example 3 (847 mg)in dimethylformamide (7 ml). The mixture was stirred for 30 minutes at100° C. The reaction mixture was poured into ice-water (30 ml). Thesolution was extracted with ethyl acetate (30 ml, 2 times). The extractwas washed with a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate and concentrated. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=3:1) to give the present compound (770 mg) having the followingphysical data.

TLC: Rf 0.27 (Hexane:Ethyl acetate=3:1); NMR (CDCl₃): δ 9.76 (1H, s),8.41 (1H, d, J=1.8 Hz), 8.02 (1H, dd, J=1.8, 8.0 Hz), 7.87 (1H, dd,J=1.6, 7.8 Hz), 7.57-7.25 (6H, m), 7.20-7.16 (1H, m), 7.10-7.05 (2H, m),6.27 (1H, brs), 5.04 (2H, s), 3.32 (2H, d, J=6.2 Hz), 1.01 (9H, s).

REFERENCE EXAMPLE 5

2′-benzyloxycarbonyl-4′-((2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Reference Example 2, usinga compound prepared in Reference Example 4.

TLC: Rf 0.38 (Chloroform:Methanol:Water=9:1:0.1).

EXAMPLE 1

Benzyl2′-(4amidinophenylcarbamoyl)-4-((2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid

Dicyclohexylcarbodiimide (513 mg), pyridine (7 ml) and 4-amidinoaniline(345 mg), successively, were added to a solution of the compoundprepared in Reference Example 5 (740 mg) in dimethylformamide (7 ml).The mixture was stirred over night. The reaction mixture was filtered,and the filtrate was concentrated. The residue was purified by columnchromatography on silica gel (Chloroform:Methanol:Water=9:1:0.1→8:2:0.1)to give the present compound (835 mg) having the following physicaldata.

TLC: Rf 0.38 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.32(1H, d, J=2.0 Hz), 7.97 (1H, dd, J=2.0, 7.6 Hz), 7.70-7.52 (7H, m), 7.43(1H, d, J=7.6 Hz), 7.30-7.26 (4H, m), 7.18-7.13 (2H, m), 5.13 (2H, s),3.20 (2H, s), 0.95 (9H, s).

EXAMPLE 2

2′-(4-amidinophenylcarbamoyl)-4-((2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

10% palladium carbon (80 mg) was added to a solution of the compoundprepared in Example 1 (814 mg) in methanol (15 ml) under an atmosphereof argon at room temperature. Hydrogen substitution was done, and themixture was stirred for 20 minutes at room temperature. The reactionmixture was filtered through celite (registered trade mark). 1Nmethanesulfonic acid in methanol (1.45 ml) was added to the filtrate,and the mixture was concentrated. The residue was crystallized withether to give the present compound (820 mg) having the followingphysical data.

TLC: Rf 0.19 (Chloroform:Methanol:Water=8:2:0.1); NMR (d₆-DMSO): δ 10.6(1H, s), 9.18 (2H, br s), 8.91 (2H, br s), 8.56 (1H, t, J=6.6 Hz), 8.31(1H, d, J=1.8 Hz), 7.99 (1H, dd, J=1.8, 8.2 Hz), 7.74-7.69 (5H, m),7.59-7.53 (2H, m), 7.33 (1H, d, J=8.0 Hz), 7.31-7.26 (1H, m), 3.12 (2H,d, J=6.6 Hz), 2.38 (3H, s), 0.90 (9H, s).

REFERENCE EXAMPLE 6

Methoxymethyl 2′-benzyloxycarbonyl-4′-methyl-2-biphenylcarboxylate

Isopropylethylamine (488 μl) was added to a solution of2′-benzyloxycarbonyl-4′-methyl-2-biphenylcarboxylic acid (880 mg) inmethylene chloride (8 ml) which was prepared by the same procedure as aseries of reaction of Reference Example 4→Reference Example 5, usingbenzyl 2-trifluoromethylsulfonyloxy-5-methylbenzoate. The mixture wascooled to 0° C., and methoxy chloride (212 μl) was added to a solution.The mixture was stirred for 30 minutes. Water was added to the reactionmixture, and the solution was extracted with chloroform. The extract waswashed with 1N hydrochloric acid and a saturated aqueous solution ofsodium chloride, successively, dried over anhydrous sodium sulfate andconcentrated to give the present compound (993 mg) having the followingphysical data.

TLC: Rf 0.41 (Hexane:Ethyl acetate=8:2); NMR (CDC₃): δ 7.98 (1H, dd,J=8.0, 1.5 Hz), 7.86 (1H, s), 7.52-7.05 (10H, m), 5.18 (1H, d, J=6.0Hz), 5.12 (1H, d, J=6.0 Hz), 5.04 (2H, s), 3.22 (3H, s), 2.43 (3H, s).

EXAMPLE 3

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-methyl-2-biphenylcarboxylate

The present compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 2 (without aprocedure of conversion to salt thereof)→Example 1, using the compoundprepared in Reference Example 6.

TLC: Rf 0.51 (Chloroform:Methanol:Acetic acid=10:2:1).

EXAMPLE 4

2′-(4-amidinophenylcarbamoyl)-4′-methyl-2-biphenylcarboxylic acidmethanesulfonate

A solution of the compound prepared in Example 3 (340 mg) in 90% aqueoussolution of trifluoroacetic acid (3 ml) was stirred for 2 hours at roomtemperature. The reaction mixture was concentrated. The residue wasdistilled off an azeotropic mixture with toluene, and was crystallizedwith a mixed solution of methanol and ether. The crystals was dissolvedwith a little of methanol. Methanesulfonic acid (53 μl), and ethylacetate was added to the solution. The mixture was stirred for 14 hours.The reaction mixture was filtered to give the present compound (182 mg)having the following physical data.

TLC: Rf 0.16 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.2-12.2 (1H, broad), 10.40 (1H, s), 9.14 (2H, brs), 8.87 (2H, brs),7.80 (1H, d, J=8 Hz), 7.74 (2H, d, J=9 Hz), 7.67 (2H, d, J=9Hz), 7.49(1H, td, J=8 Hz, 2 Hz), 7.47 (1H, s), 7.43-7.33 (2H, m), 7.20 (1H, d,J=8 Hz, 2 Hz), 7.13 (1H, d, J=8 Hz), 2.43 (3H, s), 2.35 (3H, s).

REFERENCE EXAMPLE 7

Benzyl 2-(3-methoxymethoxycarbonylnaphthalen-2-yl)benzoate

Benzyl bromide (160 μl) and potassium carbonate (202 mg) were added to asolution of 2-(3-(methoxymethoxycarbonyl)naphthalen-2-yl)benzoic acid(410 mg) which was prepared by the same procedure as a series ofreaction of Reference Example 4→Reference Example 5 using methoxymethyl2-trifluoromethylsulfonyloxy-3-naphthalenecarboxylate, indimethylformamid (5 ml). The mixture was stirred for 22 hours at roomtemperature. Water was added to the reaction mixture, and the solutionwas extracted with ethyl acetate. The extract was washed with water anda saturated aqueous solution of sodium chloride, successively, driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=8:2) togive the title compound (498 mg) having the following physical data.

TLC: Rf 0.53 (Hexane:Ethyl acetate=7:3); NMR (CDCl₃): δ 8.54 (1H, s),8.10 (1H, dd, J=8.0, 1.5 Hz), 7.94 (1H, d, J=8.0 Hz), 7.80 (1H, d, J=8.0Hz), 7.64-7.53 (4H, m), 7.46 (1H, td, J=8.0, 1.5 Hz), 7.32 (1H, dd,J=8.0, 1.5 Hz), 7.17-7.01 (3H, m), 6.95-6.90 (2H, m), 5.24 (1H, d, J=6.0Hz), 5.18 (1H, d, J=6.0 Hz), 5.05 (1H, d, J=12 Hz), 4.95 (1H, d, J=12Hz), 3.26 (3H, s).

REFERENCE EXAMPLE 8

3-(2-benzyloxycarbonylphenyl)-2-naphthalenecarboxylic acid

1N Hydrochloric acid (2.3 ml) was added to a solution of the compoundprepared in Reference Example 7 (490 mg) in dioxane (7 ml). The mixturewas stirred for 5.5 hours at 50° C. Water was added to the reactionmixture, and the solution was extracted with ethyl acetate. The extractwas washed with a saturated aqueous solution of sodium chloride, driedover anhydrous sodium sulfate and concentrated. The residue wascrystallized with hexane to give the title compound (423 mg) having thefollowing physical data.

TLC: Rf 0.16 (Hexane:Ethyl acetate=1:1); NMR (CDCl₃): δ 8.51 (1H, s),8.08 (1H, dd, J=8.0, 1.5 Hz), 7.91 (1H, d, J=8.0 Hz), 7.78 (1H, d, J=8.0Hz), 7.65-7.42 (5H, m), 7.28 (1H, dd, J=8.0, 1.5 Hz), 7.16-6.90 (5H, m),5.05 (1H, d, J=12 Hz), 4.95 (1H, d, J=12 Hz).

EXAMPLE 5

Benzyl 2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)benzoate

The present compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 1, using thecompound prepared in Reference Example 8.

TLC: Rf 0.62 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.18 (1H, s), 8.10-7.82 (3H, m), 7.78-7.52 (8H, m), 7.46 (1H, dd, J=8Hz, 2 Hz), 7.41 (1H, d, J=8 Hz), 7.18-6.90 (5H, m), 5.06 (2H, s).

EXAMPLE 6

2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)benzoic acidmethanesulfonate

The present compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 2, using thecompound prepared in Example 5.

TLC: Rf 0.64 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ12.4-12.9 (1H, broad), 10.67 (1H, s), 9.20 (2H, s), 8.98 (2H, s), 8.28(1H, s), 8.16-7.92 (2H, m), 7.87 (1H, d, J=8 Hz), 7.79 (1H, s), 7.77(4H, s), 7.70-7.50 (3H, m), 7.44 (1H, t, J=8 Hz), 7.34 (1H, d, J=8 Hz),2.36 (3H, s).

EXAMPLE 7—7(115)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 4 (using 2-formylphenylboric acid or acorresponding derivatives)→Reference Example 5→Example 1 (using4-amidinoaniline or a corresponding derivatives), using the compoundprepared in Reference Example 3 or a corresponding derivatives.

EXAMPLE 7

t-Butyl 2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.27 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ7.66-7.81 (2H, m), 7.69 (2H, d, J=9.2 Hz), 7.50-7.60 (2H, m), 7.57 (2H,d, J=9.2 Hz), 7.48 (1H, dt, J=1.8,7.6 Hz), 7.39 (1H, dt, J=1.8,7.6 Hz),7.22-7.27 (2H, m), 1.34 (9H, s).

EXAMPLE 7(1)

Benzyl 2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.57 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.85 (1H, dd, J=8 Hz, 2 Hz), 7.68-7.62 (3H, m), 7.57-7.13 (13H, m), 5.13(2H, s).

EXAMPLE 7(2)

Benzyl 3-(4-amidinophenylcarbamoyl)-4-biphenylcarboxylate

TLC: Rf 0.54 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.12 (1H, d, J=8 Hz), 7.91-7.68 (8H, m), 7.55-7.40 (3H, m), 7.38-7.28(2H, m), 7.26-7.16 (3H, m), 5.28 (2H, s).

EXAMPLE 7(3)

Benzyl 4-(4-amidinophenylcarbamoyl)-3-biphenylcarboxylate

TLC: Rf 0.51 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.24 (1H, d, J=2 Hz), 7.96 (1H, dt, J=8 Hz, 2 Hz), 7.91-7.64 (7H, m),7.56-7.41 (3H, m), 7.36-7.29 (2H, m), 7.24-7.16 (3H, m), 5.29 (2H, s).

EXAMPLE 7(4)

Benzyl 3′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.57 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.04 (2H, d, J=9 Hz), 7.97-7.80 (3H, m), 7.85 (2H, d, J=9 Hz), Hz), 7.64(1H, td, J=8 Hz, 2 Hz), 7.55-7.43 (4H, m), 7.24-7.18 (3H, m), 7.11-7.06(2H, m), 5.09 (2H, s).

EXAMPLE 7(5)

Benzyl2,3-dihydro-2,2-dimethyl-5-(2-(4-amidinophenylcarbamoyl)phenyl)-6-benzofurancarboxylate

TLC: Rf 0.44 (Chloroform:Methanol:Acetic acid=20:2:1); NMR (CD₃OD): δ7.72-7.39 (7H, m), 7.35-7.12 (6H, m), 7.08 (1H, s), 7.07 (1H, s), 5.12(2H, s), 1.43 (3H, brs), 1.38 (3H, brs).

EXAMPLE 7(6)

Benzyl 2′-(4-amidinophenylcarbamoyl)-3-biphenylcarboxylate

TLC: Rf 0.61 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.17 (1H, s), 7.95 (1H, d, J=8 Hz), 7.76-7.46(10H, m), 7.45-7.30 (5H,m), 5.30 (2H, s).

EXAMPLE 7(7)

Dibenzyl 2′-(4-amidinophenylcarbamoyl)-2,3-biphenyldicarboxylate

TLC: Rf 0.65 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.67 (1H, s), 9.50-8.95 (3H, broad), 7.91 (1H, dd, J=8 Hz, 2 Hz),7.82-7.68 (5H, m), 7.68-7.46 (4H, m), 7.45-7.30 (5H, m), 7.30-7.16 (4H,m), 7.02-6.90 (2H, m), 5.24 (2H, s), 5.00-4.65 (2H, broad).

EXAMPLE 7(8)

Benzyl 2′-(4-amidinophenylcarbamoyl)-6-m ethyl-2-biphenylcarboxylate

TLC: Rf 0.61 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.72-7.62 (4H, m), 7.58-7.45 (4H, m), 7.42-7.22 (7H, m), 7.11-7.02 (1H,m), 5.22 (1H, d, J=11 Hz), 5.15 (1H, d, J=11 Hz), 1.98 (3H, s).

EXAMPLE 7(9)

Benzyl 2′-(4-amidinophenylcarbamoyl)-5-methoxy-2-biphenylcarboxylate

TLC: Rf 0.32(Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.74(1H, s), 9.07 (3H, br.s), 7.80 (1H, d, J=8.8 Hz), 7.74 (2H, d, J=9.4Hz), 7.70 (2H, d, J=9.4 Hz), 7.62 (1H, dd, J=2.2,7.0 Hz), 7.47-7.54 (2H,m), 7.23-7.32 (4H, m), 7.03-7.07 (2H, m), 6.96 (1H, dd, J=2.6,8.8 Hz),6.82 (1H, d, J=2.6 Hz), 4.99 (2H, s), 3.80 (3H, s).

EXAMPLE 7(10)

Benzyl 2′-(4-amidinophenyIcarbamoyl)-4-methoxy-2-biphenylcarboxylate

TLC: Rf 0.30 (Chloroform:Methanol:Water=8:2:0.2); NMR (OD₃OD): δ 7.67(2H, d, J=8.8 Hz), 7.63 (1H, m), 7.54 (2H, d, J=8.8 Hz), 7.45-7.49 (2H,m), 7.36 (1H, d, J=2.6 Hz), 7.25-7.30 (4H, m), 7.06-7.23 (4H, m), 5.14(2H, s), 3.81 (3H, s).

EXAMPLE 7(11)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-biphenylcarboxylate

TLC: Rf 0.41 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.01 (2H, d, J=8.5 Hz), 7.70 (4H, s), 7.68-7.50 (6H, m), 7.46-7.32 (5H,m), 5.33 (2H, s).

EXAMPLE 7(12)

Benzyl 2′-(4-amidinophenylcarbamoyl)-6-methoxy-2-biphenylcarboxylate

TLC: Rf 0.34 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.67(2H, d, J=8.8 Hz), 7.67(1H, m), 7.52 (2H, d, J=8.8 Hz), 7.38-7.50 (4H,m), 7.28-7.34 (3H, m), 7.04-7.20 (4H, m), 5.15 (1H, d, J=12.0 Hz), 5.08(1H, d, J=12.0 Hz), 3.63 (3H, s).

EXAMPLE 7(13)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-benzyloxy-2-biphenylcarboxylate

TLC: Rf 0.41 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.67(2H, d, J=8.8 Hz), 7.63 (1H, m), 7.54 (2H, d, J=8.8 Hz), 7.14-7.49 (16H,m), 5.12 (2H, s), 5.10 (2H, s).

EXAMPLE 7(14)

Benzyl 2′-(4-amidinophenylcarbamoyl)-5-benzyloxy-2-biphenylcarboxylate

TLC: Rf 0.43 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.50(1H, s), 9.21 (1.5H, s), 8.96 (1.5H, s), 7.81 (1H, d, J=8.4 Hz), 7.76(4H, s), 7.65 (1H, m), 7.48-7.55 (2H, m), 7.24-7.40 (9H, m), 7.03-7.08(3H, m), 6.93 (1H, d, J=2.6 Hz), 5.15 (2H, s), 5.00 (2H, s).

EXAMPLE 7(15)

Benzyl 2′-(4-amidinophenylcarbamoyl)-5-methyl-2-biphenylcarboxylate

TLC: Rf 0.44 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ9.11 (2H, s), 8.87 (2H, s), 7.61 (4H, t, J=8.0 Hz), 7.52 (1H, dd, J=2.0,8.0 Hz), 7.45 (1H, d, J=8.5 Hz), 7.42 (1H,t, J=8.0 Hz), 7.38 (1H, t,J=8.0 Hz), 7.20-7.03 (5H, m), 7.01 (1H, brs), 6.92 (1H, d, J=7.5 Hz),6.91 (1H, d, J=8.0 Hz), 4.87 (2H, s), 2.22 (3H, s).

EXAMPLE 7(16)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-methyl-2-biphenylcarboxylate

TLC: Rf 0.44 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ9.15 (2H, brs), 8.89 (2H, s), 7.66 (4H, brs), 7.60-7.47 (2H, m), 7.45(1H, brt, J=8.0 Hz), 7.31 (1H, d, J=8.0 Hz), 7.26-7.02 (5H, m),7.02-6.90 (2H, m), 4.93 (2H, s), 2.26 (3H, s).

EXAMPLE 7(17)

Benzyl 2′-(4-amidinophenylcarbamoyl)-3-benzyloxy-2-biphenylcarboxylate

TLC: Rf 0.43 (Chloroform:Methanol:Water=8:2:0.2); NMR (CDCl₃): δ 7.67(1H, m), 7.66 (2H, d, J=8.8 Hz), 7.45-7.56 (2H,m), 7.53 (2H, d, J=8.8Hz), 7.13-7.39 (12H, m), 7.09 (1H, d, J=8.4 Hz), 6.82 (1H, d, J=6.8 Hz),5.15 (2H, s), 4.86 (2H, s).

EXAMPLE 7(18)

Benzyl2′-(4-amidinophenylcarbamoyl)-4′-methyl-5-chloro-2-biphenylcarboxylate

TLC: Rf 0.42 (Chloroform:Methanol=4:1); NMR (CDCl₃): δ 9.29 (1H, s),8.80 (2H, s), 8.59 (2H, s), 7.72 (2H, d, J=8.2 Hz), 7.49 (1H, s), 7.40(2H, d, J=8.2 Hz), 7.4-7.1 (9H, m), 6.94 (1H, d, J=8.2 Hz), 5.10 (2H,s), 2.36 (3H, s).

EXAMPLE 7(19)

Benzyl 2′-(4-amidinophenylcarbamoyl)-3-methoxy-2-biphenylcarboxylate

TLC: Rf 0.27 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.67(2H, d, J 8.8 Hz), 7.66 (1H, m), 7.43-7.55 (2H, m), 7.52 (2H, d, J=8.8Hz), 7.27-7.40 (4H, m), 7.16-7.22 (3H, m), 7.03 (1H, d, J=8.4 Hz), 6.80(1H, d, J=7.0 Hz), 5.15 (2H, s), 3.84 (3H, s).

EXAMPLE 7(20)

Benzyl2′-(4-amidinophenylcarbamoyl)-4′-methyl-4-methoxy-2-biphenylcarboxylate

TLC: Rf 0.34 (Chloroform:Methanol=4:1); NMR (CDCl₃): δ 8.95 (2H, brs),8.44 (1H, brs), 7.72 (2H, brs), 7.45 (1H, s), 7.4-7.3 (6H, m), 7.17 (2H,d, J=6.4 Hz), 7.07 (1H, d, J=8.4 Hz), 6.96 (1H, s), 6.60 (2H, d, J=8.8Hz), 5.17 (2H, s), 3.74 (3H, s), 2.40 (3H, s).

EXAMPLE 7(21)

Benzyl 2-(2-(4-amidinophenylcarbamoyl)phenyl)-1-naphthalenecarboxylate

TLC: Rf 0.34 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.62(1H,s), 9.09 (3H, br.s),7.98-8.05 (2H, m), 7.78-7.90 (2H, m), 7.73 (4H,s), 7.57-7.63 (4H, m), 7.46 (1H, d, J=8.4 Hz), 7.35 (1H, m), 7.26-7.29(3H, m), 7.08-7.12 (2H, m), 5.16 (2H, br.s).

EXAMPLE 7(22)

Benzyl 2′-(4-amidinophenylcarbamoyl)-3-methyl-2-biphenylcarboxylate

TLC: Rf 0.56 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ9.09 (2H, brs), 8.82 (1H, s), 8.33 (2H, brs), 7.82-7.60 (3H, m),7.52-7.03 (12H, m), 6.98 (1H, dd, J=1.0, 8.5 Hz), 5.15 (1H, d, J=10 Hz),5.03 (1H, d, J=10 Hz), 2.40 (3H, s).

EXAMPLE 7(23)

Benzyl3-(2-(4-amidinophenylcarbamoyl)phenyl)-7-methoxy-2-naphthalenecarboxylate

TLC: Rf 0.48 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.53 (1H, br.s), 9.08 (3H, br.s), 8.33 (1H, s), 7.89 (1H, d, J=9.2 Hz),7.7-7.4 (10H, m), 7.4-7.2 (4H, m), 7.2-7.0 (2H, m), 5.06 (2H, br.s),3.87 (3H, s).

EXAMPLE 7(24)

Benzyl3-(2-(4-amidinophenylcarbamoyl)phenyl)-5-methoxy-2-naphthalenecarboxylate

TLC: Rf 0.42 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.56 (1H, s), 9.06 (3H, br.s), 8.38 (1H, s), 8.02 (1H, s), 7.8-7.4(10H, m), 7.3-7.2 (3H, m), 7.2-7.0 (3H, m), 5.07 (2H, s), 3.94 (3H, s).

EXAMPLE 7(25)

Dibenzyl 2′-(4-amidinophenylcarbamoyl)-2,4-biphenyldicarboxylate

TLC: Rf 0.45 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.50(1H, d, J=1.8 Hz), 8.18 (1H, dd, J=1.8,8.0 Hz), 7.67 (2H, d, J=9.0 Hz),7.61 (2H, d, J=9.0 Hz), 7.10-7.54 (15H, m), 5.37 (2H, s), 5.11 (2H, s).

EXAMPLE 7(26)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-dimethylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.30 (Chloroform:Methanol:Water 8:2:0.2); NMR (CD₃OD): δ 7.90(1H, d, J=1.8 Hz), 7.50-7.70 (8H, m), 7.42 (1H, d, J=8.0 Hz), 7.25-7.31(4H, m), 7.12-7.16 (2H, m), 5.12 (2H, s), 3.09 (3H, s), 2.92 (3H, s).

EXAMPLE 7(27)

Benzyl3-(2-(4-amidinophenylcarbamoyl)phenyl)-6-methoxy-2-naphthalenecarboxylate

TLC: Rf 0.51 (Chloroform:Methanol:Water=10:3:0.2).

EXAMPLE 7(28)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-methylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.24 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.32(1H, d, J=1.8 Hz), 7.96 (1H, dd, J=1.8, 8.0 Hz), 7.67 (2H, d, J=8.8 Hz),7.65 (1H, m), 7.58 (2H, d, J=8.8 Hz), 7.49-7.55 (2H, m), 7.42 (1H, dJ=8.0 Hz), 7.24-7.30 (4H, m), 7.13-7.18 (2H, m), 5.16 (2H, s), 2.91 (3H,s).

EXAMPLE 7(29)

Benzyl3-(2-(4-amidinophenylcarbamoyl)phenyl)-8-methoxy-3-naphthalenecarboxylate

TLC: Rf 0.43 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.57 (1H, s), 9.3-8.8 (3H, br), 8.62 (1H, s), 7.80 (1H, s), 7.8-7.4(10H, m), 7.4-7.2 (3H, m), 7.2-7.0 (3H, m), 5.07 (2H, br.s), 3.98 (3H,s).

EXAMPLE 7(30)

Benzyl 2′-(4-amidinophenylcarbamoyl)-3,4-dimethoxy-2-biphenylcarboxylate

TLC: Rf 0.70 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.71-7.62 (3H, m), 7.54 (2H, d, J=9.0 Hz), 7.50 (1H, td, J=7.5 Hz, 1.5Hz), 7.43 (1H, td, J=7.5 Hz, 1.5 Hz), 7.33-7.16 (6H, m), 7.06 (1H, d,J=9.0 Hz), 6.94 (1H, d, J=9.0 Hz), 5.17 (2H, s), 3.80 (3H, s), 3.77 (3H,s).

EXAMPLE 7(31)

Benzyl6-(2-(4-amidinophenylcarbamoyl)phenyl)-1,2-methylenedioxybenzene-5-carboxylate

TLC: Rf 0.70 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.69 (2H, d, J=9.0 Hz), 7.62-7.55 (3H, m), 7.51-7.41 (2H, m), 7.31-7.22(4H, m), 7.22-7.10 (3H, m), 6.72 (1H, s), 6.03 and 6.00 (2H, brs), 5.08(2H, s).

EXAMPLE 7(32)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4′-nitro-2-biphenylcarboxylate

TLC: Rf 0.62 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.32 (1H, d, J=2.5 Hz), 8.19 (1H, dd, J=8.5 Hz, 2.5 Hz), 8.01-7.96 (1H,m), 7.71 (2H, d, J=9.0 Hz), 7.63 (2H, d, J=9.0 Hz), 7.60 (1H, td, J=7.5Hz, 1.5 Hz), 7.48 (1H, td, J=7.5 Hz, 1.5 Hz), 7.44 (1H, d, J=8.5 Hz),7.33 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.24-7.66 (5H, m), 5.06 and 5.04 (2H,s).

EXAMPLE 7(33)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-((benzyloxycarbonylmethyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.40 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.37(1H, d, J=1.8 Hz), 8.00 (1H, dd, J=1.8,8.0 Hz), 7.67 (2H, d, J=9.2 Hz),7.66 (1H, m), 7.59 (2H, d, J=9.2 Hz), 7.50-7.55 (2H, m), 7.4 (1H, d,J=8.0 Hz), 7.25-7.37 (9H, m), 7.13-7.18 (2H, m), 5.20 (2H, s), 5.14 (2H,s), 4.16 (2H, s).

EXAMPLE 7(34)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((1-benzyloxycarbonyl-2-phenylethyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.44 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.23(1H, d, J=1.8 Hz), 7.86 (1H, dd, J=1.8,7.8 Hz), 7.67 (2H, d, J=9.0 Hz),7.66 (1H, m), 7.59 (2H, d, J=9.0 Hz), 7.49-7.54 (2H, m), 7.39 (1H, d,J=7.8 Hz), 7.27-7.29 (8H, m), 7.18-7.20 (8H, m), 5.15 (2H, s), 5.13 (2H,s), 4.83 (1H, dd, J=6.2,9.2 Hz), 3.27 (1H, dd, J=6.2,13.8 Hz), 3.10 (1H,dd, J=9.2,13.8 Hz).

EXAMPLE 7(35)

Dibenzyl 2′-(4-amidinophenylcarbamoyl)-2-biphenylphosphorate

TLC: Rf 0.80 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.96-7.84 (1H, m), 7.68-7.20 (21H, m), 4.90-4.82 (4H, m).

EXAMPLE 7(36)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-fluoro-2-biphenylcarboxylate

TLC: Rf 0.35 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ7.58-7.72 (6H, m), 7.47-7.55 (2H, m), 7.22-7.34 (6H, m), 7.11-7.16 (2H,m), 5.12 (2H, s).

EXAMPLE 7(37)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-benzylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.22 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD: δ 8.37(1H, d, J=1.8 Hz), 8.00 (1H, dd, J=1.8,8.0 Hz), 7.65-7.69 (3H, m), 7.59(2H, d, J=9.2 Hz), 7.50-7.55 (2H, m), 7.42 (1H, d, J=8.0 Hz), 7.24-7.34(9H, m), 7.13-7.17 (2m), 5.13 (2H, s), 4.56 (2H, s).

EXAMPLE 7(38)

Benzyl2′-(4-amidinophenylcarbamoyl-4-phenylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.55 (Chloroform:Methanol:Water=7:3:0.3); NMR (CD₃OD): δ 8.28(1H, d, J=2.0 Hz), 7.92 (1H, dd, J=2.0,8.0 Hz), 7.66-7.70 (3H, m), 7.59(2H, d, J=9.2 Hz), 7.49 -7.54 (2H, m), 7.41 (1H, d, J=8.0 Hz), 7.13-7.30(11H, m), 5.13 (2H, s), 3.58 (2H, t, J=7.0 Hz) 2.89 (2H, t, J=7.0 Hz).

EXAMPLE 7(39)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-((1E)-2-methoxycarbonylethenyl)-2-biphenylcarboxylate

TLC: Rf 0.32 (Chloroform:Methanol=4:1); NMR (CDCl₃+CD₃OD): δ 7.97 (1H,s), 7.8-7.5 (6H, m) 7.6-7.4 (2H, m), 7.4-7.2 (7H, m), 7.11 (1H, d, J=6.6Hz), 6.46 (1H d, J=16.2 Hz), 5.24 (2H, d, J=5.6 Hz), 3.80 (3H, s).

EXAMPLE 7(40)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-(2-methoxyethoxy)-2-biphenylcarboxylate

TLC: Rf 0.62 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.47 (1H, br.s), 9.11 (3H, br.s), 7.8-7.4 (3H, m), 7.73 (4H, like s),7.4-7.1 (7H, m), 7.1-7.0 (2H, m), 5.01 (2H, s), 4.12 (2H, t, J=4.4 Hz),3.64 (2H, t, J=4.4 Hz), 3.33 (3H, s).

EXAMPLE 7(41)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.26 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.33(1H, d, J=1.6 Hz), 7.97 (1H, dd, J=1.6,8.0 Hz), 7.65-7.70 (3H, m), 7.59(2H, d, J=8.8 Hz), 7.50-7.54 (2H, m), 7.42 (1H, d, J=8.0 Hz), 7.26-7.29(4H, m), 7.15-7.18 (2H, m), 5.14 (2H, s), 3.18 (2H, d, J=6.8 Hz), 1.92(1H, m), 0.95 (6H, d, J=6.8 Hz).

EXAMPLE 7(42)

Benzyl2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.31 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.30(1H, d, J=1.8 Hz), 7.97 (1H, dd, J=1.8,8.0 Hz), 7.68 (2H, d, J=9.2 Hz),7.59 (2H, d, J=9.2 Hz), 7.42 (1H, d, J=8.0 Hz), 7.25-7.30 (3H, m),7.14-7.20 (4H, m), 7.06 (1H, dd, J=1.8,8.0 Hz), 5.14 (2H, s), 4.47 (1H,d, J=7.0 Hz), 3.90 (3H, s), 3.74 (3H, s), 2.25 (1H, m), 1.02 (3H, d,J=7.0 Hz), 1.00 (3H, d, J=7.0 Hz).

EXAMPLE 7(43)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-trifluoromethyloxy-2-biphenylcarboxylate

TLC: Rf 0.38 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ7.73-7.11 (16H, m), 5.11 (2H, s).

EXAMPLE 7(44)

Benzyl2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-((1-methoxycarbonyl-2-methylpropyl)carbamoyl)benzoate

TLC: Rf 0.34 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.39(1H, d, J=1.8 Hz), 8.21 (1H, s), 8.00-8.07 (2H, m), 7.88 (1H, m), 7.75(1H, s), 7.71 (4H, s), 7.62-7.66 (2H, m), 7.53 (1H, d, J=7.8 Hz),6.92-7.13 (5H, m), 5.06 (2H, s), 4.50 (1H, d, J=7.0 Hz), 3.75 (3H, s),2.27 (1H, m), 1.04 (3H, d, J=6.6 Hz), 1.02 (3H, d, J=6.6 Hz).

EXAMPLE 7(45)

Benzyl3-(2-(4-amidinophenylcarbamoyl)phenyl)-8-(2-methoxyethoxy)-2-naphthalenecarboxylate

TLC: Rf 0.32 (Chloroform:Methanol:Water 10:3:0.2); NMR (d₆-DMSO): δ10.58 (1H, s), 9.09 (3H, br.s), 8.65 (1H, s), 7.79 (1H, s), 7.75-7.65(5H, m), 7.65-7.4 (5H, m), 7.3-7.2 (3H, m), 7.2-7.0 (3H, m), 5.04 (2H,br.s), 4.4-4.2 (2H, m), 3.8-3.7 (2H, m), 3.32 (3H, s).

EXAMPLE 7(46)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((isopropylcarbonyl)aminomethyl)-2-biphenylcarboxylate

TLC: Rf 0.32 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ7.76-7.42 (9H, m), 7.30-7.14 (7H, m), 5.12 (2H, s), 4.38 (2H, s),2.53-2.40 (1H, m), 1.09 (6H, d, J=6.8 Hz).

EXAMPLE 7(47)

Benzyl2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-((2-methylpropyl)carbamoyl)benzoate

TLC: Rf 0.35 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.38(1H, d, J=2.0 Hz), 8.22 (1H, s), 8.00-8.06 (2H, m), 7.90 (1H, m), 7.76(1H, s), 7.71 (4H, s), 7.62-7.69 (3H, m), 7.53 (1H, d, J=8.0 Hz),6.91-7.13 (4H, m), 5.06 (2H, s), 3.21 (2H, d, J=7.0 Hz), 1.94 (1H, m),0.97 (6H, d, J=6.6 Hz).

EXAMPLE 7(48)

Benzyl2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.38 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.29(1H, d, J=2.0 Hz), 7.94 (1H, dd, J=2.0,8.0 Hz), 7.67 (2H, d, J=9.2 Hz),7.58 (2H, d, J=9.2 Hz), 7.40 (1H, d, J=8.0 Hz), 7.25-7.30 (3H, m),7.15-7.19 (4H, m), 7.05 (1H, dd, J=2.6, 8.8 Hz), 5.14 (2H, s), 3.89 (3H,s), 3.18 (2H, d, J=7.0 Hz), 1.91 (1H, m), 0.95 (6H, d, J=6.6 Hz).

EXAMPLE 7(49)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-isopropylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.19 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.30(1H, d, J=1.8 Hz), 7.96 (1H, dd, J=1.8, 7.6 Hz), 7.70-7.50 (7H, m), 7.41(1H, d, J=8.0 Hz), 7.29-7.26 (4H, m), 7.18-7.12 (2H, m), 5.14 (2H, s),4.19 (1H, quintet, J=6.6 Hz), 1.24 (6H, d, J=6.6 Hz).

EXAMPLE 7(50)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((3-methylbutyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.34 (Chloroform:Methanol:Water 8:2:0.1); NMR (CD₃OD): δ 8.31(1H, d, J=1.8 Hz), 7.96 (1H, dd, J=1.8, 8.0 Hz), 7.69-7.50 (7H, m), 7.42(1H, d, J=8.0 Hz), 7.29-7.26 (4H, m), 7.18-7.12 (2H, m), 5.13 (2H, s),3.43-3.29 (2H, m), 1.75-1.60 (1H, m), 1.60-1.45 (2H, m), 0.95 (6H, d,J=6.6 Hz).

EXAMPLE 7(51)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-ethylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.29 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.32(1H, d, J=1.8 Hz), 7.97 (1H, dd, J=1.8, 8.0 Hz), 7.69-7.50 (7H, m), 7.42(1H, d, J=8.0 Hz), 7.29-7.26 (4H, m), 7.17-7.15 (2H, m), 5.13 (2H, s),3.45-3.35 (2H, m), 1.21 (3H, t, J=7.4 Hz).

EXAMPLE 7(52)

Benzyl 2′-(4-amidinophenylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.36 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.31(1H, d, J=1.8 Hz), 7.97 (1H, dd, J=1.8, 8.0 Hz), 7.70-7.50 (7H, m), 7.42(1H, d, J=8.0 Hz), 7.29-7.25 (4H, m), 7.18-7.12 (2H, m), 5.13 (2H, s),3.40-3.32 (2H, m), 1.65-1.30 (4H, m), 0.96 (3H, t, J=7.4 Hz).

EXAMPLE 7(53)

Benzyl2′-(4-amidinophenylcarbamoyl)-4′-methyl-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.33 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.31(1H, d, J=1.8 Hz), 7.95 (1H, dd, J=1.8,8.0 Hz), 7.67 (2H, d, J=8.8 Hz),7.59 (2H, d, J=8.8 Hz), 7.47 (1H, m), 7.39 (1H, d, J=8.0 Hz), 7.35 (1H,m), 7.25-7.31 (3H, m), 7.11-7.17 (3H, m), 5.13 (2H, s), 3.18 (2H, d,J=6.8 Hz), 2.46 (3H, s), 1.91 (1H, m), 0.95 (6H, d, J=6.6 Hz).

EXAMPLE 7(54)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((cyclohexylmethyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.38 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.31(1H, d, J=1.8 Hz), 7.97 (1H, dd, J=1.8, 8.0 Hz), 7.69-7.50 (7H, m), 7.42(1H, d, J=8.0 Hz), 7.29-7.26 (4H, m), 7.18-7.15 (2H, m), 5.13 (2H, s),3.20 (2H, d, J=7.0 Hz), 1.85-1.40 (6H, m), 1.40-0.90 (5H, m).

EXAMPLE 7(55)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-(t-butoxycarbonylaminopentyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.43 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.32(1H, d, J=1.8 Hz), 7.97 (1H, dd, J=1.8, 8.0 Hz), 7.70-7.50 (7H, m), 7.42(1H, d, J=8.0 Hz), 7.29-7.25 (4H, m), 7.18-7.13 (2H, m), 5.13 (2H, s),3.40-3.32 (2H, m), 3.03 (2H, t, J=6.6 Hz), 1.70-1.30 (6H, m), 1.41 (9H,s).

EXAMPLE 7(56)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((1-methylpropyl)carbamoyl)-2-biphenylcarboxylate.

TLC: Rf 0.33 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.31(1H, d, J=2.0 Hz), 7.97 (1H, dd, J=2.0, 8.0 Hz), 7.70-7.50 (7H, m), 7.42(1H, d, J=8.0 Hz), 7.29-7.25 (4H, m), 7.18-7.13 (2H, m), 4.01 (1H,sextet, J=6.6 Hz), 1.66-1.51 (2H, m), 1.21 (3H, d, J=6.6 Hz), 0.94 (3H,t, J=7.2 Hz).

EXAMPLE 7(57)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((tetrahydropyran-4-methyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.48 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.31 (1H, d, J=2.0 Hz), 7.97 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.69-7.65 (3H,m), 7.60 (2H, d, J=9.0 Hz), 7.57-7.47 (2H, m), 7.42 (1H, d, J=8.0 Hz),7.29-7.23 (4H, m), 7.17-7.12 (2H, m), 5.12 (2h, brs), 3.93 (2H, dd, J=11Hz, 2.5 Hz), 3.83 (2H, td, J=11 Hz, 2.0 Hz) 3.26 (2H, d, J=7.0 Hz),1.96-1.80 (1H, m), 1.65 (2H, dd, J=13 Hz), 1.40-1.24 (2H, m).

EXAMPLE 7(58)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-((2-benzyloxycarbonyloxypropyl)carbamoyl)-2-buphenylcarboxylate

TLC: Rf 0.52 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.31(1H, d, J=1.8 Hz), 7.92 (1H, dd, J=1.8, 8.0 Hz), 7.68-7.51 (7H, m), 7.41(1H, d, J=8.2 Hz), 7.28-7.25 (9H, m), 7.17-7.14 (2H, m), 5.12 (2H, s),5.07 (2H, s), 5.07-4.90 (1H, m), 3.61 (1H , dd, J=4.0, 14.0 Hz), 3.47(1H, dd, J=7.4, 14.0 Hz), 1.30 (3H, d, J=6.4 Hz).

EXAMPLE 7(59)

Benzyl 2′-(4-amidino-2-benzyloxyphenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.71 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.43 (1H, d, J=8.5 Hz), 8.24 (1H, d, J=2.0 Hz), 7.86 (1H, dd, J=8.0 Hz,2.0 Hz), 7.69-7.65 (1H, m), 7.51-7.42 (2H, m), 7.38-7.29 (5H, m), 7.27(1H, d, J=1.5 Hz), 7.25-7.16 (5H, m), 7.13-7.09 (1H, m), 7.02-6.98 (2H,m), 5.06 (1H, d, J=12 Hz), 5.01 (1H, d, J=12 Hz), 4.94 (1H, d, J=12 Hz),4.86 (1H, d, J=12 Hz), 3.18 (2H, d, J 7.0 Hz), 1.98-1.84 (1H, m), 0.95(6H, d, J=6.5 Hz).

EXAMPLE 7(60)

Benzyl2′-(4-amidinophenylcarbamoyl)-4(N-methyl-N-(2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.43 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 7.87(1H, br s), 7.71-7.41 (9H, m), 7.31-7.26 (4H, m), 7.15-7.13 (2H, m),5.13 (2H, s), 3.40-3.31 (2H, m, each of rotamers), 3.30-3.05 (2H, m,each of rotamers), 3.05 (3H, s, each of rotamers), 2.89 (3H, s, each ofrotamers), 2.20-1.80 (1H, m), 0.98 (3H, d, J=6.6 Hz, each of rotamers),0.65 (3H, d, J=6.6 Hz, each of rotamers).

EXAMPLE 7(61)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-((2-methyl-1-(N-methyl-N-benzyloxycarbonylaminomethyl)propyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.54 (Chloroform:Methanol:Water 10:3:0.2); NMR (d₆-DMSO): δ10.68 (1H,br.s),9.4-8.8 (3H, br),′8.5-8.2 (1H, br), 8.24 (1H, br.s),8.1-7.9 (1H, br), 7.8-7.6 (5H, m), 7.56 (2H, m), 7.40 (1H, d, J=8.2 Hz),7.4-7.1 (9H, m), 7.1-7.0 (2H, m), 5.03 (2H, s), 4.97 (2H, s), 4.2-4.0(1H, br), 3.7-3.2 (2H, m), 2.9-2.7 (3H, m), 1.75 (1H, m), 1.0-0.8 (6H,m).

EXAMPLE 7(62)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((2-hydroxy-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.40 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.35(1H, d, J=2.2 Hz), 8.01 (1H, dd, J=2.2, 8.0 Hz), 7.70-7.61 (5H, m),7.55-7.50 (2H, m), 7.44 (1H, d, J=8.0 Hz), 7.30-7.20 (4H, m), 7.18-7.13(2H, m), 5.13 (2H, s), 3.40 (2H,, s), 1.22 (6H, s).

EXAMPLE 7(63)

Benzyl 2′-(4-amidino-2-methylphenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.61 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.35 (1H, d, J=2.0 Hz), 7.99 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.76-7.70 (1H,m), 7.69 (1H, d, J=8.0 Hz), 7.58-7.48 (4H, m), 7.45 (1H, d, J=8.0 Hz),7.30-7.21 (4H, m), 7.21-7.10 (2H, m), 5.14 (2H,s), 3.19 (2H, d, J=7.0Hz), 1.95 (3H, s), 2.02-1.81 (1H, m), 0.95 (6H, d, J=6.5 Hz).

EXAMPLE 7(64)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((cyclopropylmethyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.27 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.34(1H, d, J=2.0 Hz), 7.98 (1H, dd, J=2.0,8.0 Hz), 7.50-7.70 (7H, m), 7.42(1H, d, J=8.0 Hz), 7.25-7.30 (4H, m), 7.14-7.19 (2H, m), 5.14 (2H, s),3.23 (2H, d, J=7.0 Hz), 1.09 (1H, m), 0.47-0.56 (2H, m), 0.23-0.30 (2H,m).

EXAMPLE 7(65)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((1-(methylcarbamoyl)-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.36 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.33(1H, d, J=1.5 Hz), 8.01 (1H, dd, J=1.5, 7.8 Hz), 7.68-7.65 (4H, m),7.61-7.58 (2H, m), 7.53-7.50 (2H, m), 7.44 (1H, d, J=7.8 Hz), 7.28-7.26(3H, m), 7.17-7.14 (2H, m), 5.13 (2H, s), 4.27 (1H, d, J=8.1 Hz), 2.75(3H, s), 2.14 (1H, sextet, J=8.1 Hz), 1.01-0.97 (6H, m).

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((cyclopentylmethyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.30 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.32(1H, d, J=2.0 Hz), 7.96 (1H, dd, J=2.0,8.0 Hz), 7.67 (2H, d, J=8.4 Hz),7.59 (2H, d, J=8.4 Hz), 7.50-7.55 (2H, m), 7.41 (1H, d, J=8.0 Hz),7.25-7.29 (4H, m), 7.13-7.18 (3H, m), 5.14 (2H, s), 3.29 (2H, d, J=6.8Hz), 2.21 (1H, m), 1.56-1.79 (6H, m), 1.27-1.31 (2H, m).

EXAMPLE 7(67)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((cyclobutylmethyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.31 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.31(1H, d, J=2.0 Hz), 7.95 (1H, dd, J=2.0,8.0 Hz), 7.67 (2H, d, J=9.2 Hz),7.59 (2H, d, J=9.2 Hz), 7.49-7.54 (2H, m), 7.41 (1H, d, J=8.0 Hz),7.24-7.29 (4H, m), 7.13-7.17 (3H, m), 5.13 (2H, s), 3.39 (2H, d, J=7.0Hz), 2.61 (1H, m), 1.76-2.11 (6H, m).

EXAMPLE 7(68)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)sulfamoyl)-2-biphenylcarboxylate

TLC: Rf 0.43 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.30(1H, d, J=1.5 Hz), 7.91 (1H, d, J=7.5 Hz), 7.65-7.60 (5H, m), 7.60-7.50(3H, m), 7.30-7.20 (4H, m), 7.20-7.10 (2H, m), 5.12 (2H, s), 2.63 (2H,d, J=6.6 Hz), 1.70-1.60 (1H, m), 0.83 (6H, d, J=6.6 Hz).

EXAMPLE 7(69)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-5-chloro-2-biphenylcarboxylate

TLC: Rf 0.55 (Chloroform:Methanol:Acetic acid=10:2:1).

EXAMPLE 7(70)

Methoxymethyl 3-(2-(4-amidinophenylcarbamoyl)phenyl)-2-naphthalenecarboxylate

TLC: Rf 0.46 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.56 (1H, s), 9.2-8.9 (3H, s), 8.50 (1H, s), 8.12 (1H, d, J=7.0 Hz),7.97 (1H, d, J=7.0 Hz), 7.83 (1H, s), 7.8-7.4 (10H, m), 5.16 (2H, br),3.18 (3H, s).

EXAMPLE 7(71)

t-Butyl 2′-(3-amidinophenylcarbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.39 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.07(1H, s), 7.81 (1H, dd, J=1.6,7.8 Hz), 7.73 (1H, m), 7.50-7.58 (2H, m),7.44-7.50 (3H, m), 7.36-7.41 (2H, m), 7.23-7.28 (2H, m), 1.32 (9H, s).

EXAMPLE 7(72)

t-Butyl 2-(2-(4-amidinophenylcarbamoyl)phenyl)cinnamate

TLC: Rf 0.43 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.76-7.30 (13H, m), 6.28 (1H, d, J=16 Hz), 1.43 (9H, s).

EXAMPLE 7(73)

t-Butyl 2′-(4-amidinophenylcarbamoyl)biphenyl-2-yloxyacetate

TLC: Rf 0.52 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.75-7.43 (8H, m), 7.33-7.21 (2H, m), 7.01 (1H, td, J=8.0 Hz, 1.0 Hz),6.84 (1H, d, J=8.0 Hz), 4.47 (2H, s), 1.40 (9H, s).

EXAMPLE 7(74)

Methoxymethyl3-(2-(4-amidinophenylcarbamoyl)-4-methylphenyl)-2-naphthalenecarboxylate

TLC: Rf 0.27 (Chloroform:Methanol=4:1); NMR (CDCl₃): δ 9.38 (1H, s),8.68 (2H, brs), 8.35 (3H, s), 7.80 (1H, dd, J=7.0, 2.2 Hz), 7.7-7.6 (2H,m), 7.56 (2H, d, J=8.4 Hz), 7.5-7.4 (2H, m), 7.37 (2H, d, J=8.4 Hz),7.22 (1H, dd, J=7.6, 2.0 Hz), 7.05 (1H, d, J=7.6 Hz), 5.37 (1H, d, J=6.0Hz), 5.30 (1H, d, J=6.0 Hz), 3.35 (3H, s), 2.35 (3H, s).

EXAMPLE 7(75)

Methoxymethyl1-(2-(4-amidinophenylcarbamoyl)phenyl)-2-naphthalenecarboxylate

TLC: Rf 0.65 (Chloroform:Methanol:Acetic acid=10:2:1).

EXAMPLE 7(76)

Methoxymethyl2-(3-(4-amidinophenylcarbamoyl)-6-methoxynaphthalen-2-yl)benzoate

TLC: Rf 0.51 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.74 (1H, br.s), 9.4-9.0 (3H, br), 8.16 (1H, s), 8.0-7.7 (3H, m), 7.79(4H, like s), 7.63 (1H, m), 7.6-7.2 (4H, m), 5.07 (2H, br.s), 3.91 (3H,s), 3.03 (3H, s).

EXAMPLE 7(77)

Methoxymethyl3-(2-(4-amidinophenylcarbamoyl)-4-methoxyphenyl)-2-naphthalenecarboxylate

TLC: Rf 0.55 (Chloroform:Methanol:Acetic acid 10:2:1); NMR (CD₃OD): δ8.44 (1H, s), 7.96 (1H, dd, J=7.0 Hz, 2.0 Hz), 7.87 (1H, dd, J=7.0 Hz,2.0 Hz), 7.79 (1H, s), 7.65-7.50 (6H, m), 7.31 (1H, d, J=8.5 Hz, 7.25(1H, d, J=2.5 Hz), 7.15 (1H, dd, J=8.5 Hz, 2.5 Hz), 5.32 (2H, s), 3.91(3H, s), 3.36 (3H, s).

EXAMPLE 7(78)

Methoxymethyl3-(2-(4-amidinophenylcarbamoyl)-4-propoxyphenyl)-2-naphthalenecarboxylate

TLC: Rf 0.65 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.44(1H, s), 7.96(1H, dd, J=7.0 Hz, 2.0 Hz), 7.87(1H, dd, J=7.0 Hz, 2.0Hz), 7.79 (1H, s), 7.65-7.50 (6H, m), 7.30 (1H, d, J=8.5 Hz), 7.24 (1H,d, J=2.5 Hz), 7.14 (1H, dd, J=8.5 Hz, 2.5 Hz), 5.32 (2H, s), 4.06 (2H,t, J=7.0 Hz), 3.36 (3H, s), 1.86 (2H, sextet, J=7.0 Hz), 1.09 (3H, t,J=7.0 Hz).

EXAMPLE 7(79)

Methoxymethyl2-(3-(4-amidinophenylcarbamoyl)-7-methoxynaphthalen-2-yl)benzoate

TLC: Rf 0.71 (Chloroform:Methanol:Water=10:3:0.2).

EXAMPLE 7(80)

Methoxymethyl2-(3-(4-amidinophenylcarbamoyl)-5-methoxynaphthalen-2-yl)benzoate

TLC: Rf 0.54 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.80 (1H, s), 9.3-9.1 (3H, br), 8.44 (1H, s), 7.88 (1H, dd, J=1.4, 7.4Hz), 7.79 (4H, s), 7.7-7.3 (6H, m), 7.10 (1H, m), 5.07 (2H, br.s), 4.03(3H, s), 3.03 (3H, s).

EXAMPLE 7(81)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4-nitro-2-biphenylcarboxylate

TLC: Rf 0.46 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.71 (1H, d, J=2.5 Hz), 8.41 (1H, dd, J=8.5 Hz, 2.5 Hz), 7.81-7.52 (8H,m), 7.37 (1H, dd, J=8.0 Hz, 1.5 Hz), 5.23 (2H, s), 3.22 (3H, s).

EXAMPLE 7(82)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4-methylsulfonylamino-2-biphenylcarboxylate

TLC: Rf 0.44 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.49(1H, brs), 10.2-9.8 (1H, broad), 9.3-8.9 (3H, broad), 7.80-7.22 (11H,m), 5.10 (2H, s), 3.12 (3H, s), 2.99 (3H, s).

EXAMPLE 7(83)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4-chloro-2-biphenylcarboxylate

TLC: Rf 0.29 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.88(1H, d, J=2.0 Hz), 7.71 (4H, s), 7.68 (1H, m), 7.52-7.61 (3H, m),7.30-7.35 (2H, m), 5.22 (2H, s), 3.24 (3H, s).

EXAMPLE 7(84)

Methyl 2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxylate hydrochloride

TLC: Rf 0.45 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.52 (1H, s), 9.29 (2H, brs), 9.12 (2H, brs), 7.82-7.25 (12H, m), 3.51(3H, s).

EXAMPLE 7(85)

Ethyl2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylatemethanesulfonate

TLC: Rf 0.23 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.56(1H, s), 9.15 (2H, s), 8.85 (2H, s), 8.66 (1H, br.t, J=6.2 Hz), 8.24(1H, d, J=2.0 Hz), 8.03 (1H, dd, J=2.0,8.0 Hz), 7.74 (4H, s), 7.70 (1H,dd, J=2.0,8.0 Hz), 7.61 (1H, dt, J=2.0,8.0 Hz), 7.55 (1H, dt, J=2.0,8.0Hz), 7.41 (1H, d, J=8.0 Hz), 7.32 (1H, dd, J=2.0,8.0 Hz), 4.00 (2H, q,J=6.6 Hz), 3.10 (2H, t, J=6.2 Hz), 2.36 (3H, s), 1.86 (1H, m), 0.91 (3H,t, J=6.6 Hz), 0.89 (6H, d, J=6.4 Hz).

EXAMPLE 7(86)

Methyl 2′-(4-amidinophenylcarbamoyl)biphenyl-2-ylacetate

TLC: Rf 0.57 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.76-7.64 (3H, m), 7.59-7.51 (4H, m), 7.42-7.35 (2H, m), 7.29-7.16 (3H,m), 4.09 (1H, d, J=17 Hz), 3.74 (1H, d, J=17 Hz), 3.52 (3H, s).

EXAMPLE 7(87)

Ethyl 2′-(4-amidinophenylcarbamoyl)-5-nitro-2-biphenylcarboxylate

TLC: Rf 0.29 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.27(1H, dd, J=2.2, 8.4 Hz), 8.19 (1H, d, J=2.2 Hz), 7.78-7.59 (7H, m), 7.38(1H, dd, J=1.8, 8.4 Hz), 4.11 (2H, q, J=7.4 Hz), 1.02 (3H, t, J=7.4 Hz).

EXAMPLE 7(88)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-(N-methyl-N-(t-butoxycarbonyl)aminomethyl)-2-biphenylcarboxylate

TLC: Rf 0.40 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.76(1H, br.s), 7.62-7.68 (3H, m), 7.40-7.56 (5H, m), 7.27-7.33 (5H, m),7.14-7.19 (2H, m), 5.13 (2H, s), 4.44 (2H, br.s), 2.73 (3H, br.s), 1.36(9H, br.s).

EXAMPLE 7(89)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-ethoxycarbonylmethoxy-2-biphenylcarboxylate

TLC: Rf 0.63 (Chloroform:Methanol:Water 10:3:0.2); NMR (d₆-DMSO): δ10.51 (1H, s), 9.14 (3H, br.s), 7.9-7.6 (5H, m), 7.6-7.4 (2H, m),7.4-7.1 (7H, m), 7.1-7.0 (2H, m), 5.01 (2H, s), 4.84 (2H, s), 4.13 (2H,q, J=7.0 Hz), 1.16 (3H, t, J=7.0 Hz).

EXAMPLE 7(90)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.41 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.34(1H, d, J=1.8 Hz), 8.00 (1H, dd, J=1.8,8.0 Hz), 7.59-7.71 (5H, m),7.50-7.55 (2H, m), 7.43 (1H, d, J=7.8 Hz), 7.26-7.29 (4H, m), 7.13-7.18(2H, m), 5.13 (2H, s), 4.47 (1H, d, J=6.8 Hz), 3.74 (3H, s), 2.25 (1H,m), 1.02 (3H, d, J=7.0 Hz), 1.00 (3H, d, J=7.0 Hz).

EXAMPLE 7(91)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-(2-(methoxymethoxy)ethoxy)-2-biphenylcarboxylate

TLC: Rf 0.53 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.47 (1H, s), 9.12 (3H, br.s), 7.8-7.6 (4H, m), 7.7-7.5 (1H, m),7.6-7.4 (2H, m), 7.3-7.1 (7H, m), 7.1-6.9 (2H, m), 5.01 (2H, s), 4.59(2H, s), 4.2-4.0 (2H, m), 3.8-3.7 (2H, m), 3.24 (3H, s).

EXAMPLE 7(92)

Benzyl3-(2-(4-amidinophenylcarbamoyl)phenyl)-5-methoxymethoxy-2-naphthalenecarboxylate

TLC: Rf 0.74 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.64 (1H, s), 9.11 (3H, br.s), 8.42 (1H, s), 8.06 (1H, s), 7.8-7.6 (6H,m), 7.6-7.4 (4H, m), 7.3-7.1 (4H, m), 7.2-7.0 (2H, m), 5.38 (2H, s),5.08 (2H, s), 3.33 (3H, s).

EXAMPLE 7(93)

Benzyl3-(2-(4-amidinophenylcarbamoyl)phenyl)-8-methoxymethoxy-2-naphthalenecarboxylate

TLC: Rf 0.39 (Chloroform:Methanol:Water=10:2:0.1); NMR (d₆-DMSO): δ10.59 (1H, s), 9.09 (3H, br.s), 8.66 (1H, s), 7.81 (1H, s), 7.71 (5H,like s), 7.7-7.5 (4H, m), 7.44 (1H, m), 7.3-7.1 (4H, m), 7.1-7.0 (2H,m), 5.44 (2H, s), 5.07 (2H, s), 3.43 (3H, s).

EXAMPLE 7(94)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-(N-(t-butoxycarbonyl)-N-(2-methylpropyl)aminomethyl)-2-biphenylcarboxylate

TLC: Rf 0.51 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ7.76-7.39 (9H, m), 7.31-7.15 (7H, m), 5.13 (2H, s), 4.46 (2H, br s),2.96 (2H, d, J=7.2 Hz), 1.95-1.80 (1H, m), 1.43-1.30 (9H, m), 0.82 (6H,d, J=6.6 Hz).

EXAMPLE 7(95)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((2-methoxycarbonylethyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.49 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.30 (1H, d, J=2.0 Hz), 7.95 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.68 (2H, d,J=9.0 Hz), 7.66 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.59 (2H, d, J=9.0 Hz),7.58-7.46 (2H, m), 7.42 (1H, d, J=8.0 Hz), 7.30-7.23 (4H, m), 7.18-7.10(2H, m), 5.12 (2H, s), 3.66 (3H, s), 3.62 (2H, t, J=7.0 Hz), 2.64 (2H,t, J=7.0 Hz).

EXAMPLE 7(96)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((3-ethoxycarbonylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.54 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.32 (1H, d, J=2.0 Hz), 7.96 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.68 (2H, d,J=9.0 Hz), 7.66 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.58 (2H, d, J=9.0 Hz),7.58-7.46 (2H, m), 7.42 (1H, d, J=8.0 Hz), 7.30-7.22 (4H, m), 7.18-7.12(2H, m), 5.13 (2H, s), 4.07 (2H, q, J=7.0 Hz), 3.40 (2H, t, J=7.0 Hz),2.38 (2H, t, J=7.0 Hz), 1.90 (2H, quint, J=7.0 Hz), 1.20 (3H, t, J=7.0Hz).

EXAMPLE 7(97)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((1-t-butoxycarbonylpyperidin-4-ylmethyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.52 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.31(1H, d, J=1.5 Hz), 7.97 (1H, dd, J=1.5, 7.8 Hz), 7.69-7.59 (5H, m),7.53-7.50 (2H, m), 7.43 (1H, d, J=8.1 Hz), 7.28-7.26 (4H, m), 7.16-7.14(2H, m), 5.13 (2H, s), 4.07 (2H, d, J=12.9 Hz), 3.27-3.23 (2H, m), 2.74(2H, m), 1.90-1.70 (3H, m), 1.45 (9H, s), 1.20-1.05 (2H, m).

EXAMPLE 7(98)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((2-methylsulfinylethyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.64 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.63 (1H, s), 9.4-9.0 (3H, br), 9.03 (1H, br.t), 8.26 (1H, d, J=2.0Hz), 8.04 (1H, dd, J=2.0, 8.0 Hz), 7.8-7.6 (5H, m), 7.6-7.4 (2H, m),7.42 (1H, d, J=8.0 Hz), 7.4-7.2 (4H, m), 7.1-7.0 (2H, m), 5.04 (2H, s),3.62 (2H, m), 3.06 (1H, dt, J=13.0, 6.0 Hz), 2.87 (1H, dt, J=13.0, 6.0Hz), 2.58 (3H, s).

EXAMPLE 7(99)

Benzyl2-(4-(4-amidinophenylcarbamoyl)pyridin-3-yl)-5-((2-methylpropyl)carbamoyl)benzoate

TLC: Rf 0.45 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.63 (1H, d, J=5.0 Hz), 8.50 (1H, s), 8.43 (1H, d, J=2.0 Hz), 8.04 (1H,dd, J=8.0 Hz, 2.0 Hz), 7.72 (2H, d, J=9.0 Hz, 7.65 (2H, d, J=9.0 Hz),7.60 (1H, d, J=5.0 Hz), 7.48 (1H, d, J=8.0 Hz), 7.30-7.22 (3H, m),7.22-7.13 (2H, m), 5.11 (2H, s), 3.19 (2H, d, J=7.5 Hz), 2.02-1.81 (1H,m), 0.95 (6H, d, J=6.5 Hz).

EXAMPLE 7(100)

Ethyl 2-(2-(4-amidinophenylcarbamoyl)pyridin-3-yl)benzoate

TLC: Rf 0.50 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.96 (1H, br.s), 9.18 (3H, br.s), 8.73 (1H, d, J=4.4 Hz), 8.0-7.8 (1H,m), 7.92 (2H, d, J=8.8 Hz), 7.80 (2H, d, J=8.8 Hz), 7.8-7.6 (2H, m),7.62 (1H, d, J=7.2 Hz), 7.50 (1H, t, J=7.2 Hz, 7.29 (1H, d, J=7.2 Hz),3.93 (2H, q, J=7.4 Hz), 0.88 (3H, t, J=7.4 Hz).

EXAMPLE 7(101)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-propylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.38 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.32(1H, d, J=1.8 Hz), 7.97 (1H, dd, J=1.8, 8.0 Hz), 7.69-7.50 (8H, m), 7.42(1H, d, J=8.0 Hz), 7.29-7.26 (3H, m), 7.18-7.15 (2H, m), 5.13 (2H, s),3.35-3.29 (2H, m), 1.62 (2H, sextet, J=7.2 Hz), 0.96 (3, t, J=7.2 Hz).

EXAMPLE7(102)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((3hydroxy-2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.38 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.33(1H, d, J=2.0 Hz), 7.98 (1H, dd, J=2.0, 8.0 Hz), 7.70-7.58 (6H, m),7.55-7.50 (2H, m), 7.43 (1H, d, J=8.0 Hz), 7.29-7.26 (3H, m), 7.17-7.10(2H, m), 5.13 (2H, s), 3.29-3.24 (4H, m), 0.92 (6H, s).

EXAMPLE 7(103)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((1,2,2-trimethylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.33 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.28(1H, d, J=1.8 Hz), 7.93 (1H, dd, J=1.8,8.0 Hz), 7.66-7.69 (3H, m), 7.61(2H, d, J=9.0 Hz), 7.50-7.54 (2H, m), 7.41 (1H, d, J=8.0 Hz), 7.25-7.29(4H, m), 7.14-7.17 (2H, m), 5.13 (2H, s), 4.05 (1H, q, J=7.0 Hz), 1.16(3H, d, J=7.0 Hz), 0.96 (9H, s).

EXAMPLE 7(104)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-pentylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.32 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.31(1H, d, J=2.0 Hz), 7.96 (1H, dd, J=2.0,8.0 Hz), 7.66-7.68 (3H, m), 7.61(2H, d, J=9.0 Hz), 7.50-7.54 (2H, m), 7.42 (1H, d, J=8.0 Hz), 7.26-7.28(4H, m), 7.14-7.17 (2H, m), 5.13 (2H, s),3.35 (2H, t, J=7.0 Hz),1.59-1.63 (2H, m), 1.33-1.38 (4H, m), 0.90-0.95 (3H, m).

EXAMPLE 7(105)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-hexylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.48 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.32(1H, d, J=1.8 Hz), 7.97 (1H, dd, J=1.8, 8.0 Hz), 7.70-7.49 (8H, m), 7.42(1H, d, J=8.0 Hz), 7.29-7.26 (3H, m), 7.18-7.13 (2H, m), 5.13 (2H, s),3.39-3.30 (2H, m), 1.70-1.50 (2H, m), 1.50-1.20 (6H, m), 0.90 (3H, t,J=6.6 Hz).

EXAMPLE 7(106)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((1,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: :Rf 0.45 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.31(1H, d, J=1.8 Hz), 7.96 (1H, dd, J=1.8, 8.0 Hz), 7.70-7.50 (8H, m), 7.41(1H, d, J=8.0 Hz), 7.29-7.26 (3H, m), 7.18-7.13 (2H, m),5.14 (2H, s),3.91 (1H, m), 1.80 (1H, sextet, J=6.6 Hz), 1.18 (3H, d, J=6.6 Hz), 0.95(6H, d, J=6.6 Hz).

EXAMPLE 7(107)

Methyl2′-(4-amidinophenylcarbamoyl)-4-(((1S)-1-hydroxymethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.49 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.63 (1H, s), 9.3-8.8 (3H, br), 8.24 (1H, d, J=1.8 Hz), 8.22 (1H, br.d,J=9.3 Hz), 8.06 (1H, dd, J=1.8, 7.8 Hz), 7.75 (4H, like s), 7.68 (1H,dd, J=1.8, 7.8 Hz), 7.60 (1H, dt, J=1.8, 7.8 Hz), 7.54 (1H, dt, J=1.8,7.8 Hz), 7.40 (1H, d, J=7.8 Hz), 7.31 (1H, dd, J=1.8, 7.8 Hz), 4.60 (1H,t, J=6.0 Hz), 3.81 (1H, m), 3.54 (3H, s), 3.6-3.4 (2H, m), 1.90 (1H,like sextet, J=6.9 Hz), 0.90 (3H, d, J=6.9 Hz), 0.87 (3H, d, J=6.9 Hz).

EXAMPLE 7(108)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((3,3-dimethylbutyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.28 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃D): δ 8.32(1H, d, J=2.0 Hz), 7.95 (1H, dd, J=2.0,8.0 Hz), 7.65-7.69 (3H, m), 7.60(2H, d, J=9.0 Hz), 7.49-7.53 (2H, m), 7.40 (1H, d, J=8.0 Hz), 7.24-7.28(4H, m), 7.13-7.16 (2H, m), 5.12 (2H, s), 3.35-3.41 (2H, m), 1.50-1.55(2H, m), 0.97 (9H, s).

EXAMPLE 7(109)

Methyl2′-(4-amidinophenylcarbamoyl)-4-(((1R)-1-hydroxymethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.49 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.63 (1H, br.s), 9.3-8.8 (3H, br), 8.24 (1H, d, J=1.5 Hz), 8.22 (1H, d,J=8.0 Hz), 8.06 (1H, dd, J=1.5, 8.0 Hz), 7.75 (4H, like s), 7.68 (1H,dd, J=1.5, 8.0 Hz), 7.60 (1H, dt, J=1.5, 8.0 Hz), 7.54 (1H, dt, J=1.5,8.0 Hz), 7.40 (1H, d, J=8.0 Hz), 7.32 (1H, dd, J=1.5, 8.0 Hz), 4.61 (1H,t, J=7.8 Hz), 3.81 (1H, m), 3.54 (3H, s), 3.6-3.4 (2H, m), 1.90 (1H,like sextet, J=6.8 Hz), 0.90 (3H, d, J=6.8 Hz), 0.86 (3H, d, J=6.8 Hz).

EXAMPLE 7(110)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-(((1S)-1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.45 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.32(1H, d, J=1.4 Hz), 8.00 (1H, dd, J=1.4, 8.0 Hz), 7.70-7.58 (5H, m),7.55-7.49 (2H, m), 7.43 (1H, d, J=8.0 Hz), 7.30-7.25 (4H, m), 7.17-7.12(2H, m), 5.12 (2H, s), 4.46 (1H, d, J=7.0 Hz), 3.73 (3H, s), 2.24 (1H,sextet, J=7.0 Hz), 1.01 (6H, dd, J=3.6, 7.0 Hz).

EXAMPLE 7(111)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-(((1R)-1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.48 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 8.32(1H, d, J=2.1 Hz), 7.99 (1H, dd, J=2.1, 8.1 Hz), 7.69-7.50 (7H, m), 7.43(1H, d, J=8.1 Hz), 7.29-7.25 (4H, m), 7.16-7.13 (2H, m), 5.12 (2H, s),4.46 (1H, d, J=6.9 Hz), 3.73 (3H, s), 2.24 (1H, sextet, J=6.9 Hz), 1.10(6H, dd, J=5.1, 6.9 Hz).

EXAMPLE 7(112)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-(3-methylbutoxy)-2-biphenylcarboxylate

TLC: Rf 0.51 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ7.69-7.41 (7H, m), 7.34-7.04 (9H, m), 5.12 (2H, s), 4.01 (2H, t, J=6.6Hz), 1.88-1.59 (3H, m), 0.94 (6H, d, J=6.6 Hz).

EXAMPLE 7(113)

Benzyl2-(3-(4-amidinophenylcarbamoyl)pyridin-4-yl)-5-((2-methylpropyl)carbamoyl)benzoate

TLC: Rf 0.33 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.77 (1H, s), 8.63 (1H, dd, J=5.0 Hz), 8.43 (1H, d, J=2.0 Hz), 8.04 (1H,dd, J=8.0 Hz, 2.0 Hz), 7.70 (4H, s), 7.43 (1H, d, J=8.0 Hz), 7.38 (1H,d, J=5.0 Hz), 7.30-7.12 (5H, m), 5.11 (2H, s), 3.19 (2H, d, J=7.0 Hz),2.02-1.81 (1H, m), 0.95 (6H, d, J=6.5 Hz).

EXAMPLE 7(114)

Benzyl2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((1,2,2-trimethylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.67 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.77 (1H, d, J=2.5 Hz), 8.25 (1H, d, J=2.0 Hz), 8.18 (1H, dd, J=8.5Hz,2.5 Hz), 8.02 (1H, d, J=8.5 Hz), 7.93 (1H, dd, J=8.0 Hz, 2.0 Hz),7.42 (1H, d, J=8.0 Hz), 7.27-7.17 (5H, m), 7.26-7.09 (2H, m), 7.08 (1H,dd, J=8.5 Hz, 2.5 Hz), 5.10 (2H, s), 4.05 (1H, q, J=7.0 Hz), 3.89 (3H,s), 1.15 (3H, d, J=7.0 Hz), 0.95 (9H, s).

EXAMPLE 7(115)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-(((1S)-1-hydroxymethyl-2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.32 (Chloroform:Methanol:Water 8:2:0.1); NMR (CD₃OD): δ 8.33(1H, d, J=1.8 Hz), 7.99 (1H, dd, J=1.8, 7.8 Hz), 7.70-7.49 (7H, m), 7.42(1H, d, J=8.0 Hz), 7.29-7.25 (4H, m), 7.18-7.13 (2H, m), 5.13 (2H, s),4.04 (1H, dd, J=3.6, 9.2 Hz), 3.87 (1H, dd, J=3.6, 11.8 Hz), 3.61 (1H,dd, J=9.0, 11.8 Hz), 0.98 (9H, s).

EXAMPLE 8-EXAMPLE 8(7)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 7→Reference Example 8→Example 1, usinga compound prepared in Reference Example 5 or a corresponding compound,with the proviso that, the compound of Example 8(6) was obtained by thesame procedure as a series of reaction of Reference Example 3 instead ofExample 1.

EXAMPLE 8

Benzyl 2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-methylbenzoate

TLC: Rf 0.20 (Chloroform:Methanol=4:1); NMR (CD₃OD): δ 8.16 (1H, s),8.1-8.0 (1H, m), 7.9-7.8 (1H, m), 7.7-7.6 (8H, m), 7.39 (1H, dd, J=6.6,1.8 Hz), 7.29 (1H, d, J=7.6 Hz), 7.2-7.0 (3H, m), 6.94 (2H, dd, J=7.6,1.0) 5.06 (2H, s), 2.39 (3H, s).

EXAMPLE 8(1)

Benzyl 2-(2-(4-amidinophenylcarbamoyl)naphthalen-1-yl)benzoate

TLC: Rf 0.75 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.03-7.92 (3H, m), 7.69-7.46 (8H, m), 7.42-7.10 (6H, m), 6.93-6.89 (2H,m), 5.02 (1H, d, J=12 Hz), 4.95 (1H, d, J=12 Hz).

EXAMPLE 8(2)

Benzyl 2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-benzoate

TLC: Rf 0.58 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.14 (1H, s), 8.02-7.97 (1H, m), 7.88-7.83 (1H, m), 7.73-7.58 (7H, m),7.41 (1H, d, J=2.5 Hz), 7.33 (1H, d, J=8.0 Hz), 7.16-6.87 (6H, m), 5.05(2H, s), 3.82 (3H, s).

EXAMPLE 8(3)

Benzyl 2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-propoxybenzoate

TLC: Rf 0.58 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.14 (1H, s), 8.03-7.97 (1H, m), 7.89-7.83 (1H, m), 7.73-7.58 (7H, m),7.39 (1H, d, J=2.5 Hz), 7.32 (1H, d, J=8.0 Hz), 7.16-6.87 (6H, m), 5.05(2H, s), 3.96 (2H, t, J=7.9 Hz), 1.79 (2H, sextet, J=7.0 Hz), 1.03 (3H,t, J=7.0 Hz).

EXAMPLE 8(4)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4′-chloro-2-biphenylcarboxylate

TLC: Rf 0.24 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.90(1H, dd, J=1.6,7.8 Hz), 7.67 (2H, d, J=9.2 Hz), 7.55-7.61 (3H, m),7.39-7.52 (3H, m), 7.28-7.33 (4H, m), 7.20 (1H, d, J=7.8 Hz, 7,14-7.17(2H, m), 5.13 (2H, s).

EXAMPLE 8(5)

Benzyl2′-(4-amidinophenylcarbamoyl)-4′-((E)-2-methoxycarbonylethenyl)-2-biphenylcarboxylate

TLC: Rf 0.19 (Chloroform:Methanol=4:1); NMR (CDCl₃): δ 9.25 (1H, s),8.82 (2H, br s), 8.56 (2H, br s), 7.81 (1H, s), 7.9-7.7 (1H, m), 7.69(2H, d, J=7.8 Hz), 7.5-7.1 (13H, m), 7.07 (1H, d, J=8.0 Hz), 6.48 (1H,d, J=16.2 Hz), 5.11 (2H, s), 3.75 (3H, s).

EXAMPLE 8(6)

Benzyl2′-(4-(N¹-t-butoxycarbonylamidino)phenylcarbamoyl)-3′-benzyloxy-2-biphenylcarboxylate

TLC: Rf 0.53 (Hexane:Ethyl acetate=1:1); NMR (CDCl₃) δ 9.80-9.00 (1H,broad), 8.37 (1H, s), 7.77 (1H, d, J=8.0 Hz), 7.62 (2H, d, J=9.0 Hz),7.47-7.15 (15H, m), 7.09 (2H, d, J=9.0 Hz), 7.02 (1H, d, J=8.0 Hz), 6.72(1H, d, J=8.0 Hz), 5.21 (1H, d, J=12 Hz), 5.20 (2H, s), 5.10 (1H, d,J=12 Hz), 1.53 (9H, s).

EXAMPLE 8(7)

Benzyl 2-(2-(4-amidinophenylcarbamoyl)benzothiophen-3-yl)benzoate

TLC: Rf 0.72 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.09 (1H, dd, J=8.0, 1.5 Hz), 7.93 (1H, d, J=8.0 Hz) 7.77-7.58 (4H, m),7.56-7.41 (4H, m), 7.34 (1H, td, J=7.0 Hz, 1.5 Hz), 7.26-7.08 (3H, m),6.97-6.90 (2H, m), 5.02 (1H, d, J=12 Hz), 4.95 (1H, d, J=12 Hz).

EXAMPLE 9-EXAMPLE 9(31)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 6→Example 2→Example 1, using a compoundprepared in Reference Example 5 or a corresponding compound.

EXAMPLE 9

Methoxymethyl 2-(2,3-dihydro-2,2-dimethyl-6-(4-amidinophenylcarbamoyl)benzofuran-5-yl)benzoate

TLC: Rf 0.33 (Chloroform:Methanol:Acetic acid=20:2:1); NMR (CD₃OD): δ7.83 (1H, d, J=8 Hz), 7.69 (2H, d, J=9 Hz), 7.58 (2H, d, J=9 Hz), 7.51(1H, t, J=8 Hz), 7.38 (1H, t, J=8 Hz), 7.31 (1H, d, J=8 Hz), 7.05 (1H,s), 6.95 (1H, s), 5.28 (2H, s), 3.30 (3H, s), 3.10 (2H, s), 1.50 (6H,s).

EXAMPLE 9(1)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-6′-methyl-2-biphenylcarboxylate

TLC: Rf 0.47 (Chloroform:Methanol:Acetic acid=10:2:1).

EXAMPLE 9(2)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-5′-methyl-2-biphenylcarboxylate

TLC: Rf 0.47 (Chloroform:Methanol:Acetic acid=10:2:1).

EXAMPLE 9(3)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-isopropyl-2-biphenylcarboxylate

TLC: Rf 0.43 (Chloroform:Methanol:Acetic acid=10:2:1).

EXAMPLE 9(4)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-t-butyl-2-biphenylcarboxylate

TLC: Rf 0.41 (Chloroform:Methanol:Acetic acid=10:2:1).

EXAMPLE 9(5)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-ethyl-2-biphenylcarboxylate

TLC: Rf 0.13 (Chloroform:Methanol:Water=9:1:0.1).

EXAMPLE 9(6)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-methoxy-2-biphenylcarboxylate

TLC: Rf 0.43 (Chloroform:Methanol:Acetic acid=10:2:1).

EXAMPLE 9(7)

Methoxymethyl 2-(5,6,7,8-tetrahydro-3-(4-amidinophenylcarbamoyl)naphthalen-2-yl) benzoate

TLC: Rf 0.25 (Chloroform:Methanol:Acetic acid=10:2:1).

EXAMPLE 9(8)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-cyano-2-biphenylcarboxylate

TLC: Rf 0.12 (Chloroform:Methanol:Acetic acid=10:2:1).

EXAMPLE 9(9)

Methoxymethyl 2-(6-(4-amidinophenylcarbamoyl)indan-5-yl) benzoate

TLC: Rf 0.24 (Chloroform:Methanol:Acetic acid=10:2:1).

EXAMPLE 9(10)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-5′-methoxy-2-biphenylcarboxylate

TLC: Rf 0.25 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.89(1H, dd, J=1.4,8.0 Hz), 7.69 (2H, d, J=9.0 Hz), 7.67 (1H, d, J=8.6 Hz),7.60 (2H, d, J=9.0 Hz), 7.57 (1H, dt, J=1.4,8.0 Hz), 7.44 (1H, dt,J=1.4,8.0 Hz), 7.34 (1H, dd, J=1.4,8.0 Hz), 7.05 (1H, dd, J=2.6, 8.6Hz), 6.80 (1H, d, J=2.6 Hz), 5.27 (2H, br.s), 3.87 (3H, s), 3.29 (3H,s).

EXAMPLE 9(11)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-6′-methoxy-2-biphenylcarboxylate

TLC: Rf 0.27 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.91(1H, dd, J=1.4,7.6 Hz), 7.68 (2H, d, J=9.2 Hz), 7.59 (2H, d, J=9.2 Hz),7.51 (1H, dt, J=1.4,7.6 Hz), 7.47 (1H, d, J=7.6 Hz), 7.38 (1H, dt,J=1.4,7.6 Hz), 7.16-7.28 (3H, m), 5.32 (2H, s), 3.72 (3H, s), 3.35 (3H,s).

EXAMPLE 9(12)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-5′-chloro-4-methyl-2-biphenylcarboxylate

TLC: Rf 0.27 (Chloroform:Methanol=4:1); NMR (CDCl₃): δ 9.46 (1H, s),8.70 (2H, s), 8.58 (2H, s), 7.72 (2H, d, J=8.4 Hz), 7.62 (2H, d, J=8.8Hz), 7.44 (2H, d, J=8.4 Hz), 7.4-7.2 (2H, m), 7.12 (1H, s), 7.09 (1H, d,J=8.6 Hz), 5.27 (2H, d, J=3.6 Hz), 3.32 (3H, s), 2.30 (3H, s).

EXAMPLE 9(13)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-methyl-2-biphenylcarboxylate

TLC: Rf 0.34 (Chloroform:Methanol=4:1); NMR (CDCl₃): δ 9.34 (1H, s),8.76 (2H, brs), 8.55 (2H, brs), 7.75 (2H, d, J=8.4 Hz), 7.59 (1H, d,J=1.4 Hz), 7.43 (2H, d, J=8.4 Hz), 7.21 (1H, d, J=8.4 Hz), 7.20 (1H, dd,J=7.8, 1.4 Hz), 7.09 (1H, d, J=7.8 Hz), 7.02 (1H, d, J=8.4 Hz), 6.93(1H, dd, J=8.4, 2.4 Hz), 5.29 (2H, d, J=6.2 Hz), 3.81 (3H, s), 3.33 (3H,s), 2.36 (3H, s).

EXAMPLE 9(14)

Methoxymethyl2-(3-(4-amidinophenylcarbamoyl)-8-methoxynaphthalen-2-yl)benzoate

TLC: Rf 0.52 (Chloroform:Methanol:Water=10:3:0.2);

NMR (d₆-DMSO): : δ 10.79 (1H, s), 9.4-8.9 (3H, br), 8.24 (1H, s), 7.97(1H, s), 7.88 (1H, dd, J=1.0, 7.6 Hz), 7.79 (4H, likes), 7.7-7.3 (5H,m), 7.10 (1H, d, J=7.0 Hz), 5.08 (2H, br.s), 3.97 (3H, s), 3.05 (3H, s).

EXAMPLE 9(15)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-dimethylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.30 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.96(1H, dd, J=1.6,7.8 Hz), 7.56-7.74 (7H, m), 7.35-7.51 (3H, m), 5.25 (2H,s), 3.30 (3H, s), 3.16 (3H, br.s), 3.13 (3H, br.s).

EXAMPLE 9(16)

Bis(methoxymethyl)2′-(4-amidinophenylcarbamoyl)-2,4′-biphenyldicarboxylate

TLC: Rf 0.27 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.33(1H, d, J=1.8 Hz), 8.24 (1H, dd, J=1.8,7.8 Hz), 7.98 (1H, dd, J=1.4,7.8Hz), 7.73 (2H, d, J=9.0 Hz), 7.67 (2H, d, J=9.0 Hz), 7.62 (1H, dt,J=1.4,7.8 Hz), 7.48 (1H, dt, J=1.4,7.8 Hz), 7.47 (1H, d, J=7.8 Hz), 7.37(1H, dd, J=1.4,7.8 Hz), 5.53 (2H, s), 5.24 (2H, s), 3.57 (3H, s), 3.29(3H, s).

EXAMPLE 9(17)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-methylcarbamoyl-2-biphenylcarboxylate

TLC: Rf 0.20 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.15(1H, d, J=1.8 Hz), 8.00 (1H, dd, J=1.4,8.0 Hz), 7.96 (1H, dd, J=1.4,8.0Hz), 7.73 (2H, d, J=9.0 Hz), 7.67 (2H, d, J=9.0 Hz), 7.60 (1H, dt,J=1.4,8.0 Hz), 7.47 (1H, dt, J=1.4,8.0 Hz), 7.42 (1H, d, J=8.0 Hz), 7.36(1H, dd, J=1.4,8.0 Hz), 5.23 (2H, s), 3.26 (3H, s), 2.98 (3H, s).

EXAMPLE 9(18)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-methylaminomethyl-2-biphenylcarboxylate

TLC: Rf 0.26 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.90(1H, dd, J=1.8,7.8 Hz), 7.53-7.73 (6H, m), 7.39-7.48 (2H, m), 7.33 (1H,dd, J=1.8,7.8 Hz), 7.29 (1H, d, J=7.8 Hz), 5.26 (2H, s), 4.56 (2H, s),3.29 (3H, s), 2.92 (3H, s), 1.50 (9H, s).

EXAMPLE 9(19)

Methoxymethyl 2-(6-(4-amidinophenylcarbamoyl)-1, 2-methylenedioxybenzen-5-yl)benzoate

TLC: Rf 0.53 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.86 (1H, dd, J=8.0 Hz, 1.5 Hz), 7.68 (2H, d, J=9.0 Hz), 7.56 (2H, d,J=9.0 Hz), 7.54 (1H, td, J=8.0 Hz, 1.5 Hz), 7.40 (1H, td, J=8.0 Hz, 1.5Hz), 7.32 (1H, dd, J=8.0 Hz, 1.5 Hz), 7.15 (1H, s), 6.74 (1H, s), 6.09(2H, s), 5.29 (2H, s), 3.36 (3H, s).

EXAMPLE 9(20)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-(2-methoxymethoxyethoxy)-2-biphenylcarboxylate

TLC: Rf 0.66 (Chloroform:Methanol:Water=10:2:0.1); NMR (d₆-DMSO): δ10.51 (1H, s), 9.3-8.9 (3H, br.d), 7.9-7.6 (5H, m), 7.56 (1H, dt, J=1.6,7.4 Hz), 7.42 (1H, dt, J=1.6, 7.4 Hz), 7.4-7.1 (4H, m), 5.11 (2H, br.s),4.65 (2H, s), 4.24 (2H, t, J=5.0 Hz), 3.83 (2H, t, J=5.0 Hz), 3.29 (3H,s), 3.16 (3H, s).

EXAMPLE 9(21)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-fluoro-2-biphenylcarboxylate

TLC: Rf 0.29 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.92(1H, dd, J=1.6,7.8 Hz), 7.71 (2H, d, J=9.2 Hz), 7.63 (2H, d, J=9.2 Hz),7.56 (1H, m), 7.40-7.49 (2H, m), 7.30-7.37 (3H, m), 5.26 (2H, s), 3.31(3H, s).

EXAMPLE 9(22)

Methoxymethyl 2-(3-(4-amidinophenylcarbamoyl)-8-methoxymethoxynaphthalen-2-yl)benzoate

TLC: Rf 0.49 (Chloroform:Methanol:Water=10:3:0.2).

EXAMPLE 9(23)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-(2-methoxyethoxy)-2-biphenylcarboxylate

TLC: Rf 0.70 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.50 (1H, s), 9.3-8.9 (3H, br), 7.81 (1H, dd, J=1.4, 7.8 Hz), 7.74 (4H,like s), 7.56 (1H, dt, J=1.4, 7.4 Hz), 7.42 (1H, dt, J=1.4, 7.4 Hz),7.35-7.10 (4H, m), 5.11 (2H, br.s), 4.21 (2H, t, J=4.4 Hz), 3.69 (2H, t,J=4.4 Hz), 3.32 (3H, s), 3.16 (3H, s).

EXAMPLE 9(24)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-trifluoromethoxy-2-biphenylcarboxylate

TLC: Rf 0.31 (Chloroform:Methanol:Water=8:2:0.1); NMR (CD₃OD): δ 7.95(1H, dd, J=2.0, 7.4 Hz), 7.74-7.14 (10H, m), 5.25 (2H, s), 3.29 (3H, s).

EXAMPLE 9(25)

Methoxymethyl 2-(3-(4-amidinophenylcarbamoyl)-5-(2-methoxyethoxy)naphthalen-2-yl)benzoate

TLC: Rf 0.45 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.77 (1H, s), 9.3-9.0 (3H, s), 8.40 (1H, s), 8.0-7.7 (6H, m), 7.7-7.4(5H, m), 7.12 (1H, m), 5.09 (2H, br.s), 4.35 (2H, t, J=5.0 Hz), 3.83(2H, t, J=5.0 Hz), 3.36 (3H, s), 3.06 (3H, s).

EXAMPLE 9(26)

Methoxymethyl 2-(3-(4-amidinophenylcarbamoyl)-5-methoxymethoxynaphthalen-2-yl)benzoate

TLC: Rf 0.57 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.81 (1H, s), 9.3-9.0 (3H, br), 8.44 (1H, s), 7.78 (4H, like s),8.0-7.6 (3H, m), 7.7-7.4 (3H, m), 7.42 (1H, br.d, J=7.8 Hz), 7.22 (1H,br.d, J=6.4 Hz), 5.49 (2H, s), 5.09 (2H, br.s), 3.49 (3H, s), 3.05 (3H,s).

EXAMPLE 9(27)

Methoxymethyl 2′-(4-amidinophenylcarbamoyl)-4′-((methoxycarbonylmethyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.21 (Chloroform Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.20(1H, d, J=1.8 Hz), 8.06 (1H, dd, J=1.8,7.8 Hz), 7.97 (1H, dd, J=1.8,7.8Hz), 7.72 (2H, d, J=9.2 Hz), 7.67 (2H, d, J=9.2 Hz), 7.61 (1H, dt,J=1.8,7.8 Hz), 7.48 (1H, dt, J=1.8,7.8 Hz), 7.44 (1H, d, J=7.8 Hz), 7.37(1H, dd, J=1.8,7.8 Hz), 5.23 (2H, s), 4.18 (2H, s), 3.77 (3H, s), 3.27(3H, s).

EXAMPLE 9(28)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-((1-methoxycarbonyl-2-phenylethyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.37 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.06(1H, d, J=1.6 Hz), 7.95 (1H, dd, J=1.6,7.6 Hz), 7.94 (1H, dd, J=1.6,7.6Hz), 7.72 (2H, d, J=9.0 Hz), 7.66 (2H, d, J=9.0 Hz), 7.60 (1H, dt,J=1.6,7.6 Hz), 7.46 (1H, dt, J=1.6,7.6 Hz), 7.39 (1H, d, J=7.6 Hz), 7.35(1H, dd, J=1.6,7.6 Hz), 7.20-7.29 (5H, m), 5.22 (2H, s), 4.92 (1H, m),3.75 (3H, s), 3.23 (3H, s), 3.09-3.39 (2H, m).

EXAMPLE 9(29)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-ethoxycarbonylmethoxy-2-biphenylcarboxylate

TLC: Rf 0.50 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ10.51 (1H, s), 9.3-8.9 (3H, br), 7.9-7.6 (5H, m), 7.57 (1H, dt, J=1.4,7.4 Hz), 7.42 (1H, dt, J=1.4, 7.4 Hz), 7.4-7.1 t3H, m), 7.12 (1H, dd,J=2.6, 8.4 Hz), 5.11 (2H, s), 4.91 (2H, s), 4.19 (2H, q, J=7.4 Hz), 3.14(3H, s), 1.22 (3H, t, J=7.4 Hz).

EXAMPLE 9(30)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-((1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.33 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.18(1H, d, J=1.8 Hz), 8.06 (1H, dd, J=1.8,7.8 Hz), 7.97 (1H, dd, J=1.8,7.8Hz), 7.73 (2H, d, J=9.2 Hz), 7.67 (2H, d, J=9.2 Hz), 7.61 (1H, dt,J=1.8,7.8 Hz), 7.48 (1H, dt, J=1.8,7.8 Hz), 7.43 (1H, d, J=7.8 Hz), 7.36(1H, dd, J=1.8,7.8 Hz), 5.25 (2H, s), 4.56 (1H, m), 3.78 (3H, s), 3.29(3H, s), 2.30 (1H, m), 1.06 (3H, d, J=6.8 Hz), 1.04 (3H, d, J=6.8 Hz).

EXAMPLE 9(31)

A mixture of Methoxymethyl2-(6-(4-amidinophenylcarbamoyl)-1-benzyloxymethylbenzoimidazol-5-yl)benzoateand Methoxymethyl2-(5-(4-amidinophenylcarbomoyl-1-benzylmethylbenzoimidazol-6-yl)benzoate

TLC: Rf 0.23 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.46(0.5H, s), 8.43 (0.5H, s), 8.03 (0.5H, s), 7.98 (0.5H, s), 7.93 (0.5H,dd, J=1.2,7.5 Hz),7.90 (0.5H, dd, J=1.2,7.5 Hz), 7.71 (1H, d, J=9.0 Hz),7.70 (1H, d, J=9.0 Hz), 7.66 (1H, d, J=9.0 Hz), 7.63 (1H, d, J=9.0 Hz),7.59 (0.5H, dt, J=1.2,7.5 Hz), 7.58 (0.5H, dt, J=1.2,7.5 Hz), 7.57(0.5H, s), 7.52 (0.5H, s), 7.46 (0.5H, dt, J=1.2,7.5 Hz), 7.44 (0.5H,dt, J=1.2,7.5 Hz), 7.41 (0.5H, dd, J=1.2,7.5 Hz), 7.40 (0.5H, dd,J=1.2,7.5 Hz), 7.30 (2.5H, s), 7.25 (2.5H, s), 5.85 (1H, s), 5.78 (1H,s), 5.24 (1H, br.s), 5.18 (1H, br.s), 4.60 (1H, s), 4.55 (1H, s), 3.22(1.5H, s), 3.15 (1.5H, s).

EXAMPLE 10

2′-(4-amidinophenylcarbamoyl)-4′-((1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

The present compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 4, using acompound prepared in Example 9(30).

TLC: Rf 0.42 (Chloroform:Methanol:Water=7:3:0.3); NMR (CD₃OD): δ 8.17(1H, d, J=1.8 Hz), 8.02 (1H, dd, J=1.8,7.8 Hz), 7.92 (1H, dd, J=1.8,7.8Hz), 7.71 (2H, d, J=9.2 Hz), 7.62 (2H, d, J=9.2 Hz), 7.54 (1H, dt,J=1.8,7.8 Hz), 7.44 (1H, dt, J=1.8,7.8 Hz), 7.36 (1H, d, J=7.8 Hz), 7.28(1H, dd, J=1.8,7.8 Hz), 4.55 (1H, d, J=6.4 Hz), 3.77 (3H, s), 2.70 (3H,s), 2.29 (1H, m), 1.06 (3H, d, J=6.4 Hz), 1.04 (3H, d, J=6.4 Hz).

EXAMPLE 11

2′-(4-amidinophenylcarbamoyl)-4′-((1-carboxy-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

2N aqueous solution of sodium hydroxide (1.5 ml) was added to a solutionof the compound prepared in Example 10 (710 mg) in methanol (10 ml). Themixture was stirred for 12 hours at room temperature. 2N hydrochloricacid was added to the reaction mixture, and the solution wasconcentrated. The residue was purified by column chromatography onsilica gel (Chloroform:Methanol:Water=7:3:0.3→Trifluoroaceticacid:dimethylformamide=1:99). 1N methanesulfonic acid (1.0 ml) was addedto the purified compound to give the present compound (652 mg) havingthe following physical data.

TLC: Rf 0.11 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.69(1H, s), 9.26 (2H, s), 9.05 (2H, s), 8.67 (1H, d, J=8.2 Hz), 8.25 (1H,s), 8.05 (1H, dd, J=1.8,8.0 Hz), 7.88 (1H, dd, J=1.8,8.0 Hz), 7.79 (2H,d, J=9.2 Hz), 7.75 (2H, d, J=9.2 Hz), 7.55 (1H, dt, J=1.8,8.0 Hz), 7.44(1H, dt, J=1.8,8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.25 (1H, dd, J=1.8,8.0Hz), 4.36 (1H, m), 2.37 (3H, s), 2.25 (1H, m), 1.02 (3H, d, J=6.8 Hz),1.00 (3H, d, J=6.8 Hz).

REFERENCE EXAMPLE 9

2′-methoxymethoxycarbonyl-4-acetoxy-2-biphenylcarboxylic acid

2′-methoxymethoxycarbonyl-4-hydroxy-2-biphenylcarboxylic acid (606 mg)which was prepared by the same procedure as a series of reaction ofReference Example 4→Reference Example 5→Reference Example 6→Example 2(without a procedure of conversion to salt thereof), using benzyl2-trifluoromethylsulfonyloxy-5-benzyloxybenzoate, was dissolved intoacetic acid anhydrous (1 ml) and pyridine (2 ml). The solution wasstirred for 12 hours at room temperature. Water (100 ml) was added tothe reaction mixture, and the solution was extracted with ethyl acetate(2 times). The extract was washed with a saturated aqueous solution ofammonium chloride, a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and concentrated to give thetitle compound (700 mg) having the following physical data.

TLC: Rf 0.31 (Chloroform:Methanol:Water=9:1:0.1);

NMR (CDCl₃): δ 8.06 (1H, dd, J=1.4,7.6 Hz), 7.82 (1H, d, J=2.8 Hz), 7.55(1H, dt, J=1.4,7.6 Hz), 7.44 (1H, dt, J=1.4,7.6 Hz), 7.19-7.36 (3H, m),5.24 (1H, d, J=6.2 Hz), 5.14 (1H, d, J=6.2 Hz), 3.22 (3H, s), 2.33 (3H,s).

REFERENCE EXAMPLE 9(1)

2′-methoxymethoxycarbonyl-5-acetoxy-2-biphenylcarboxylic acid

The title compound having the following physical data was prepared bythe same procedure as a series of reaction of Reference Example 9, using2′-methoxymethoxycarbonyl-5-hydroxy-2-biphenylcarboxylic acid which wasprepared by the same procedure as a series of reaction of ReferenceExample 4→Reference Example 5→Reference Example 4→Example 2 (without aprocedure of conversion to salt thereof), using benzyl2-trifluoromethylsulfonyloxy-4-benzyloxybenzoate.

TLC: Rf 0.38 (Chloroform:Methanol=20:1); NMR (CDCl₃): δ 8.11 (1H, d,J=8.8 Hz), 8.06 (1H, dd, J=1.4,7.6 Hz), 7.54 (1H, dt, J=1.4,7.6 Hz),7.44 (1H, dt, J=1.4,7.6 Hz), 7.23 (1H, dd, J=1.4,7.6 Hz), 7.19 (1H, dd,J=2.2,8.8 Hz), 6.98 (1H, d, J=2.2 Hz), 5.22 (1H, d, J=6.0 Hz), 5.18 (1H,d, J=6.0 Hz), 3.24 (3H, s), 2.29 (3H, s).

REFERENCE EXAMPLE 10

Methyl 2′-benzyloxycarbonyl-4′-nitro-2-biphenylcarboxylate

To a solution of 2′-benzyloxycarbonyl-4′-nitro-2-biphenylcarboxylic acid(2.8 g) which was prepared by the same procedure as a series of reactionof Reference Example 4→Reference Example 5, using Benzyl2-trifluoromethylsulfonyloxy-5-nitrobenzoate, in ether-ethyl acetate(1:1, 40 ml), diazomethane (30 ml) was added. Acetic acid was added tothe reaction mixture, and the solution was concentrated. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=5:2) to give the title compound (2.57 g) having the followingphysical data.

TLC: Rf 0.51 (Hexane:Ethyl acetate=5:2); NMR (CDCl₃): δ 8.89 (1H, d,J=2.2 Hz), 8.37 (1H, dd, J=2.2,8.4 Hz), 8.00 (1H, dd, J=1.6,7.6 Hz),7.53 (1H, dt, J=1.6,7.6 Hz), 7.43 (1H, dt, J=1.6,7.6 Hz), 7.37 (1H, d,J=8.4 Hz), 7.27-7.32 (3H, m), 7.12-7.16 (3H, m), 5.09 (2H, s), 3.60 (3H,s).

REFERENCE EXAMPLE 11

2′-benzyloxycarbonyl-4′-amino-2-biphenylcarboxylic acid

To a solution of 2′-benzyloxycarbonyl-4′-nitro-2-biphenylcarboxylic acid(2.08 g) which was prepared by the same procedure as a series ofreaction of Reference Example 4→Reference Example 5, using Benzyl2-trifluoromethylsulfonyloxy-5-nitrobenzoate, in concentrationhydrochloric acid-ethanol (5:3, 8 ml), a solution of Tin (II) chloridedihydrate (3.7 g) in ethanol (5 ml) was added. The mixture was stirredfor 1 hour at room temperature. 2N aqueous solution of sodium hydroxidewas added to the reaction solution, the solution was extracted withethyl acetate (2 times). The extract was washed with water, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography on silica gel(Chloroform:Methanol:Water=9:1:0.1→8:2:0.2) to give the title compound(1.07 g) having the following physical data.

TLC: Rf 0.57 (Chloroform:Methanol:Water=8:2:0.2); NMR (CDCl₃): δ 7.86(1H, dd, J=1.8,7.8 Hz), 7.42 (1H, dt, J=1.8,7.8 Hz), 7.31 (1H, dt,J=1.8,7.8 Hz), 7.24-7.27 (4H, m), 7.06-7.15 (3H, m), 6.95 (1H, d, J=7.8Hz), 6.77 (1H, dd, J=1.8,7.8 Hz), 5.03 (2H, s).

REFERENCE EXAMPLE 12

2′-methoxycarbonyl-4-amino-2-biphenylcarboxylic acid

To a mixed solution of the compound prepared in Reference Example 10(2.5 g) in methanol-ethyl acetate (4:1, 10 ml), 20% palladium hydroxideon carbon (160 mg) was added. The mixture was stirred for 1 hour underan atmosphere of hydrogen gas. The reaction mixture was filtered throughcelite (registered trade mark). The filtrate was concentrated. Theresidue was purified by column chromatography on silica gel(Chloroform:Methanol:Water=9:1:0.1→7:3:0.3) to give the title compound(1.15 g) having the following physical data.

TLC: Rf 0.24 (Chloroform:Methanol:Water=9:1:0.1); NMR (CD₃OD): δ 7.82(1H, dd, J=1.4,7.6 Hz), 7.49 (1H, dt, J=1.4,7.6 Hz), 7.34 (1H, dt,J=1.4,7.6 Hz), 7.27 (1H, d, J=2.0 Hz), 7.23 (1H, dd, J=1.4,7.6 Hz), 6.89(1H, d, J=8.0 Hz), 6.85 (1H, dd, J=2.0,8.0 Hz), 3.59 (3H, s).

REFERENCE EXAMPLE 13

2′-methoxycarbonyl-4-bromo-2-biphenylcarboxylic acid

To a solution of the compound prepared in Reference Example 12 (550 mg)in 48% aqueous solution of hydrogen bromide (2.7 ml), an aqueoussolution (1.4 ml) of sodium nitrate (140 mg) was added at 5-10° C.Copper bromide (160 mg) was added to the reaction mixture, and themixture was stirred for 30 minutes at 50° C. Water (50 ml) was added tothe reaction mixture, and the solution was extracted with ethyl acetate.The extract was washed with water, dried over anhydrous magnesiumsulfate and concentrated. The residue was washed with hexane to give thetitle compound (585 mg) having the following physical data.

TLC: Rf 0.63 (Chloroform:Methanol:Water=9:1:0.1); NMR (CDCl₃): δ 8.16(1H, d, J=2.2 Hz), 8.00 (1H, dd, J=1.8,7.4 Hz), 7.67 (1H, dd, J=2.2,8.4Hz), 7.54 (1H, dt, J=1.8,7.4 Hz), 7.44 (1H, dt, J=1.8,7.4 Hz), 7.16 (1H,dd, J=1.8,7.4 Hz), 7.05 (1H, d, J=8.4 Hz), 3.67 (3H, s).

REFERENCE EXAMPLE 13(1)

2′-benzyloxycarbonyl-4′-bromo-2-biphenylcarboxylic acid

The title compound was obtained by the same procedure as a series ofreaction of Reference Example 13, using the compound prepared inReference Example 11.

TLC: Rf 0.48 (Chloroform:Methanol:Water=9:1:0.1); NMR (CDCl₃): δ 8.15(1H, d, J=2.2 Hz), 7.96 (1H, dd, J=1.6,7.8 Hz), 7.61 (1H, dd, J=2.2,8.2Hz), 7.48 (1H, dt, J=1.6, 7.8 Hz), 7.36 (1H, dt, J=1.6,7.8 Hz),7.24-7.27 (3H, m), 7.08-7.13 (3H, m), 7.03 (1H, d, J=8.2 Hz), 5.02 (2H,s).

EXAMPLE 12-EXAMPLE 12(3)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 1, using the compound prepared in ReferenceExample 9-Reference Example 9(1), and Reference Example 13-ReferenceExample 13(1).

EXAMPLE 12

Methoxymethyl 2′-(4-amidinophenylcarbamoyl)-4′-acetoxy-2-biphenylcarboxylate

TLC: Rf 0.40 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.92(1H, dd, J=1.4,7.6 Hz), 7.71 (2H, d, J=9.0 Hz), 7.62 (2H, d, J=9.0 Hz),7.57 (1H, dd, J=1.4,7.6 Hz), 7.34-7.49 (5H, m), 5.24 (2H, br.s), 3.26(3H, s), 2.33 (3H, s).

EXAMPLE 12(1)

Methoxymethyl 2′-(4-amidinophenylcarbamoyl)-5′-acetoxy-2-biphenylcarboxylate

TLC: Rf 0.25 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.92(1H, dd, J=1.4,7.8 Hz), 7.61-7.74 (5H, m), 7.57 (1H, dt, J=1.4,7.8 Hz),7.45 (1H, dt, J=1.4,7.8 Hz), 7.35 (1H, dd, J=1.4,7.8 Hz), 7.27 (1H, dd,J=2.4,8.4 Hz), 7.08 (1H, d, J=2.4 Hz), 5.25 (2H, s), 3.27 (3H, s), 2.30(3H, s).

EXAMPLE 12(2)

Methoxymethyl2′-(4-amidinophenylcarbamoyl)-4′-bromo-2-biphenyl)carboxylate

TLC: Rf 0.25 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.85(1H, dd, J=1.4,7.8 Hz), 7.82 (1H, d, J=2.2 Hz), 7.72 (1H, dd, J=2.2,8.4Hz), 7.71 (2H, d, J=9.2 Hz), 7.63 (2H, d, J=9.2 Hz), 7.56 (1H, dt,J=1.4,7.8 Hz), 7.43 (1H, dt, J=1.4,7.8 Hz), 7.34 (1H, dd, J=1.4,7.8 Hz),7.21 (1H, d, J=8.4 Hz),3.69 (3H, s).

EXAMPLE 12(3)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-bromo-2-biphenylcarboxylate

TLC: Rf 0.25 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.97(1H, d, J=2.2 Hz), 7.60-7.73 (6H, m), 7.48-7.53 (2H, m), 7.22-7.29 (5H,m), 7.10-7.15 (2H, m), 5.10 (2H, s).

EXAMPLE 13

Methyl2′-(4-(N²-t-butoxycarbonylamidino)phenylcarbamoyl)-3′-methoxy-2-biphenylcarboxylate

The present compound having the following physical data was obtained bythe same procedure as a series of reaction of Reference Example4→Reference Example 5→Reference Example 10→Reference Example12→Reference Example 3, using benzyl2-trifluoromethylsulfonyloxy-6-methoxybenzoate.

TLC: Rf 0.63 (Chloroform:Methanol:Water=9:1:0.1); NMR (CDCl₃): δ 8.81(1H, s), 7.67-7.75 (1H, m), 7.68 (2H, d, J=8.6 Hz), 7.28-7.46 (4H, m),7.33 (2H, d, J=8.6 Hz), 6.99 (1H, d, J=8.4 Hz), 6.69 (1H, d, J=7.6 Hz),3.92 (3H, s), 3.84 (3H, s), 1.53 (9H, s).

EXAMPLE 14-EXAMPLE 14(2)

The following compounds having the following physical data were obtainedby the same procedure as a series of reaction of Reference Example4→Reference Example 5→Reference Example 7→Reference Example 8→ReferenceExample 5→Reference Example 3 (using a corresponding derivative insteadof 2,2-dimethylpropylamine)→Example 2→Example 1, using methyl5-(1,3-dioxoran-2-yl)-2-trifluoromethylsulfonyloxybenzoate.

EXAMPLE 14

Methyl2′-(4-amidinophenylcarbamoyl)-4-((1-dimethylaminomethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.28 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.72 (1H, s), 9.35-9.1 (3H, br), 8.73 (1H, d, J=9.4 Hz), 8.29 (1H, s),8.19 (1H, d, J=7.8 Hz), 7.78 (4H, like s), 7.71 (1H, d, J=7.8 Hz),7.7-7.5 (2H, m), 7.42 (1H, d, J=7.8 Hz), 7.29 (1H, d, J=7.8 Hz), 4.21(1H, br), 3.54 (3H, s), 3.6-3.2 (2H, br), 2.78 (3H, s), 2.77 (3H, s),1.84 (1H, m), 0.92 (3H, d, J=7.4 Hz), 0.88 (3H, d, J=7.4 Hz).

EXAMPLE 14(1)

Methyl2′-(4-amidinophenylcarbamoyl)-4-((1-(pyrrolidin-1-ylmethyl)-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.28 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.73 (1H, s), 9.4-9.1 (3H, br), 8.73 (1H, d, J=7.4 Hz), 8.30 (1H, d,J=2.0 Hz), 8.20 (1H, dd, J=2.0, 8.0 Hz), 7.9-7.6 (5H, m), 7.7-7.5 (2H,m), 7.41 (1H, d, J=8.0 Hz), 7.29 (1H, dd, J=2.0, 8.0 Hz), 4.17 (1H, br),3.54 (3H, s), 3.6-3.3 (4H, br), 3.2-3.0 (2H, br), 2.0-1.7 (5H, m), 0.92(3H, d, J=8.0 Hz), 0.88 (3H, d, J=8.0 Hz).

EXAMPLE 14(2)

Methyl2′-(4-amidinophenylcarbamoyl)-4-((1-hydroxymethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.49 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.62 (1H, br.s), 9.11 (3H, s), 8.25 (1H, s), 8.21 (1H, br), 8.06 (1H,dd, J=1.5, 7.8 Hz), 7.75 (4H, like s), 7.69 (1H, br.d, J=7.2 Hz), 7.60(1H, dt, J=1.5, 7.2 Hz), 7.54 (1H, dt, J=1.5, 7.2 Hz), 7.40 (1H, d,J=7.8 Hz), 7.31 (1H, br.d, J=7.2 Hz), 4.60 (1H, br), 4.09 (1H, br), 3.81(1H, m), 3.54 (3H, s), 3.51 (1H, m), 1.91 (1H, like sextet, J=6.6 Hz),0.90 (3H, d, J=7.0 Hz), 0.87 (3H, d, J=7.0 Hz).

REFERENCE EXAMPLE 14

Methyl 2-(6-benzyloxycarbonylbenzofuranr-5-yl)benzoate

To a solution of 2-(6-benzyloxycarbonylbenzofuran-5-yl)benzoic acid(1.12 g) which was prepared by the same procedure as a series ofreaction of Reference Example 4→Reference Example 5, using benzyl5-trifluoromethylsulfonyloxy-6-benzofurancarboxylate, indimethylformamide (12 ml), methyl iodide (205 μl) and potassiumcarbonate (455 mg) was added. The mixture was stirred for 14 hours atroom temperature. Water was added to the reaction mixture, and thesolution was extracted with ethyl acetate. The extract was washed withwater and a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate and concentrated to give the title compound(1.16 g) having the following physical data.

TLC: Rf 0.49 (Hexane:Ethyl acetate=8:2); NMR (CDCl₃): δ 8.24 (1H, d,J=1.0 Hz), 7.93 (1H, dd, J=8.0, 1.5 Hz), 7.77 (1H, d, J=2.0 Hz), 7.49(1H, td, J=8.0, 1.5 Hz), 7.38 (1H, s), 7.37 (1H, td, J=8.0, 1.5 Hz),7.32-7.14 (6H, m), 6.79 (1H, dd, J=2.0, 1.0 Hz), 5.09 (2H, s), 3.55 (3H,s).

REFERENCE EXAMPLE 14(1)

Methyl 2-(5-benzyloxycarbonylbenzofuran-6-yl)benzoate

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Reference Example 14,using 2-(5-benzyloxycarbonylbenzofuran-6-yl)benzoic acid.

TLC: Rf 0.50 (Hexane:Ethyl acetate=8:2); NMR (CDCl₃): δ 8.35 (1H, s),7.94 (1H, dd, J=8.0, 1.5 Hz), 7.68 (1H, d, J=2.0 Hz), 7.50 (1H, td,J=8.0, 1.5 Hz), 7.37 (1H, td, J=8.0, 1.5 Hz), 7.33-7.13 (7H, m), 6.85(1H, dd, J=2.0, 1.0 Hz), 5.07 (2H, s), 3.56 (3H, s).

EXAMPLE 15-EXAMPLE 15(1)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 2→Example 1, using the compounds prepared inReference Example 14→Reference Example 14(1).

EXAMPLE 15

Methyl 2-(6-(4-amidinophenylcarbamoyl)benzofuran-5-yl)benzoate

TLC: Rf 0.60 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.95(1H, d, J=2.0 Hz), 7.85(1H, d, J=1.0 Hz), 7.82 (1H, dd, J=8.0 Hz,1.5 Hz), 7.70 (2H, d, J=9.0 Hz), 7.61 (2H, d, J=9.0 Hz), 7.54 (1H, td,J=8.0 Hz, 1.5 Hz), 7.50 (1H, s), 7.40 (1H, td, J=8.0 Hz, 1.5 Hz), 7.37(1H, dd, J=8.0 Hz, 1.5 Hz), 6.94 (1H, dd, J=2.0 Hz, 1.0 Hz), 3.67 (3H,s).

EXAMPLE 15(1)

Methyl 2-(5-(4-amidinophenylcarbamoyl)benzofuran-6-yl)benzoate

TLC: Rf 0.60 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.96 (1H, s), 7.90 (1H, d, J=2.0 Hz), 7.83 (1H, dd, J=8.0 Hz, 1.5 Hz),7.70 (2H, d, J=9.0 Hz), 7.61 (2H, d, J=9.0 Hz), 7.54 (1H, td, J=8.0 Hz,1.5 Hz), 7.40 (1H, td, J=8.0 Hz, 1.5 Hz), 7.40 (1H, d, J=1.0 Hz), 7.38(1H, dd, J=8.0 Hz, 1.5 Hz), 7.00 (1H, dd, J=2.0 Hz, 1.0 Hz), 3.67 (3H,s).

REFERENCE EXAMPLE 15

Benzyl2′-hydroxymethyl-4-((2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylate

To a solution of the compound prepared in Reference Example 4 (1.65 g)in methanol (20 ml), sodium borohydride (174 mg) was added at −50° C.The mixture was stirred for 15 minutes at −50° C. Acetone was added to areaction solution, and was diluted with ethyl acetate (80 ml). Thesolution was washed with a saturated aqueous solution of sodium chloride(40 ml, 2 times), dried over anhydrous sodium sulfate and concentratedto give the present compound (1.65 g) having the following physicaldata.

TLC: Rf 0.40 (Hexane:Ethyl acetate=1:1).

REFERENCE EXAMPLE 16

Benzyl2′-bromomethyl-4-((2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylate

A solution of the compound prepared in Reference Example 15 (1.65 g) inmethylene chloride (15 ml), carbon tetrabromide (2.55 g) andtriphenylphosphine (1.51 g) were added at 0° C. The mixture was stirredfor 15 minutes at room temperature. A saturated aqueous solution ofsodium bicarbonate (50 ml) was added to the mixture, and the solutionwas extracted with ethyl acetate (50 ml, 2 times). The extract waswashed with a saturated aqueous solution of sodium chloride (100 ml),dried over anhydrous sodium sulfate and concentrated. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=3:1) to give the title compound (1.45 g) having the followingphysical data.

TLC: Rf 0.56 (Hexane:Ethyl acetate=1:1).

EXAMPLE 16

Benzyl2′-(4-(N²-benzyloxycarbonylamidino)phenylaminomethyl)-4-((2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylate

The compound prepared in Reference Example 16 (900 mg), potassiumcarbonate (301 mg), sodium iodide (273 mg) and4-(N²-benzyloxycarbonyamidino)aniline (587 mg) were dissolved intodimethylformamide (20 ml). The mixture was stirred for 65 hours at roomtemperature. The reaction mixture was diluted with ethyl acetate (100ml), and washed with a saturated aqueous solution of sodium chloride(150 ml; three times). The organic layer was dried over anhydrous sodiumsulfate and concentrated. The residue was purified by columnchromatography on silica gel (Chloroform:Ethyl acetate=3:1). Theobtained solid was washed with ether to give the present compound (667mg) having the following physical data.

TLC: Rf 0.83 (Chloroform:Methanol=10:1); NMR (d₆-DMSO): δ 9.4-8.4 (2H,br), 8.57 (1H, br), 8.37 (1H, d, J=1.8 Hz), 8.09 (1H, dd, J=1.8, 8.0Hz), 7.72 (2H, d, J=9.0 Hz), 7.49 (1H, d, J=8.0 Hz), 7.4-7.2 (11H, m),7.2-7.1 (2H, m), 7.05 (1H, d, J=8.0 Hz), 6.57 (1H, br), 6.41 (2H, d,J=9.0 Hz), 5.12 (2H, s), 5.05 (2H, s), 3.98 (2H, br.s), 3.12 (2H, d,J=6.6 Hz), 0.90 (9H, s).

EXAMPLE 17-EXAMPLE 17(10)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 15→Reference Example 16→Example 16,using a corresponding derivatives instead of the starting compound inReference Example 15.

EXAMPLE 17

Benzyl2′-(4-(N²-benzyloxycarbonylamidino)phenylaminomethyl)-2-biphenylcarboxylate

TLC Rf 0.68 (Chloroform:Ethyl acetate=8:2); NMR (CDCl₃): δ 9.7-9.2 (1H,broad), 7.95 (1H, dd, J=8.0 Hz, 1.5 Hz), 7.62-7.05 (19H, m), 6.25 (2H,d, J=9.0 Hz), 5.19 (2H, s), 5.13 (1H, d, J=12 Hz), 5.03 (1H, d, J=12Hz), 4.37 (1H, t, J=5.0 Hz), 4.04 (2H, d, J=5.0 Hz).

EXAMPLE 17(1)

Benzyl 2-(3-(4-(N²-benzyloxycarbonylamidino)phenylaminomethyl)naphthalen-2-yl)benzoate

TLC: Rf 0.18 (Toluene:Ethyl acetate=6:1); NMR (d₆-DMSO): δ 9.4-8.4 (2H,br), 8.0-6.8 (23H, m), 6.46 (2H, d, J=8.8 Hz), 5.12 (1H, d, J=12.8 Hz),5.05 (2H, s), 5.03 (1H, d, J=12.8 Hz), 4.11 (2H, d, J=4.8 Hz).

EXAMPLE 17(2)

Benzyl2′-(4-(N²-benzyloxycarbonylamidino)phenylaminomethyl)-4′-methoxy-2-biphenylcarboxylate

TLC:Rf 0.56 (Chloroform:Ethyl acetate=8:2); NMR (CDCl₃): δ 9.8-9.2 (1H,broad), 7.92 (1H, dd, J=8.0 Hz, 1.5 Hz), 7.60 (2H, d, J=9.0 Hz),7.52-7.10 (13H, m), 7.01 (1H, d, J=8.0 Hz), 6.90 (1H, d, J=2.5 Hz), 6.81(1H, dd, J=8.0 Hz, 2.5 Hz), 6.27 (2H, d, J=9.0 Hz), 5.19 (2H, s), 5.13(1H, d, J=12 Hz), 5.06 (1H, d, J=12 Hz), 4.38 (1H, brt, J=7.0 Hz), 4.00(2H, d, J=7.0 Hz), 3.81 (3H, s).

EXAMPLE 17(3)

Benzyl 2-(3-(4-(N²-benzyloxycarbonylamidino)phenylaminomethyl)naphthalen-2-yl)-5-((2-methylpropyl)carbamoyl)benzoate

TLC: Rf 0.41 (Hexane:Ethyl acetate=2:3); NMR (CDCl₃): δ 8.22 (1H, d,J=2.0 Hz), 7.74-7.90 (4H, m), 7.42-7.58 (8H, m), 7.31-7.36 (3H, m),7.08-7.23 (3H, m), 6.89-6.92 (2H, m), 6.21-6.25 (3H, m), 5.19 (2H, s),5.05 (1H, d, J=12.0 Hz), 5.00 (1H, d, J=12.0 Hz), 4.31 (1H, br.t, J=5.2Hz), 4.19 (2H, br.d, J=5.2 Hz), 3.28 (2H, t, J=6.6 Hz), 1.90 (1H, m),0.97 (6H, d, J=6.6 Hz).

EXAMPLE 17(4)

Benzyl2′-(4-(N²-benzyloxycarbonylamidino)phenylaminomethyl)-4′-methoxy-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.37(Hexane:Ethyl acetate=2:3); NMR (CDCl₃): δ 8.21 (1H, d,J=2.0 Hz), 7.84 (1H, dd, J=2.0,8.0 Hz), 7.52 (2H, d, J=8.8 Hz),7.41-7.46 (2H, m), 7.24-7.36 (7H, m), 7.10-7.15 (2H, m), 6.97 (1H, d,J=8.4 Hz), 6.88 (1H, d, J=2.6 Hz), 6.80 (1H, dd, J=2.6,8.4 Hz), 6.39(1H, br.t, J=6.6 Hz), 6.18 (2H, d, J=8.8 Hz), 5.18 (2H, s), 5.12 (1H, d,J=12.0 Hz), 5.06 (1H, d, J=12.0 Hz), 4.27 (1H, br.t, J=5.0 Hz), 3.98(2H, br.t, J=5.0 Hz), 3.81 (3H, s), 3.24 (2H, t, J=6.6 Hz), 1.87 (1H,m), 0.94 (6H, d, J=6.6 Hz).

EXAMPLE 17(5)

Benzyl2′-(4-(N²-benzyloxycarbonylamidino)phenylaminomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.70 (Chloroform:Ethyl acetate=1:1); NMR (d₆-DMSO): δ 9.3-8.6(2H, broad), 8.69 (1H, brt, J=5.5 Hz), 8.37 (1H, d, J=2.0 Hz), 8.08 (1H,dd, J=8.0 Hz, 2.0 Hz), 7.71 (2H, d, J=9.0 Hz), 7.48 (1H, d, J=8.0 Hz),7.40-7.20 (11H, m), 7.18-7.09 (2H, m), 7.05 (1H, d, J=7.5 Hz), 6.76 (1H,brt, J=5.5 Hz), 6.40 (2H, d, J=9.0 Hz), 5.11 (2H, s), 5.05 (2H, s), 3.97(2H, d, J=5.5 Hz), 3.10 (2H, t, J=6.0 Hz), 1.85 (1H, m), 0.88 (6H, d,J=6.5 Hz).

EXAMPLE 17(6)

Ethyl 2′-(4-(N²-ethoxycarbonylamidino)phenylaminomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate methanesulfonate

TLC: Rf 0.42 (Chloroform:Ethyl acetate=1:1); NMR (d₆-DMSO): δ 11.80 (1H,brs), 10.61 (1H, brs), 9.99 (1H, brs), 8.70 (1H, brt, J=6.0 Hz), 8.34(1H, d, J=2.0 Hz), 8.07 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.60-7.46 (1H,broad), 7.57 (2H, d, J=8.5 Hz), 7.50 (1H, d, J=8.0 Hz), 7.38-7.26 (3H,m), 7.07 (1H, d, J=7.5 Hz), 6.53 (2H, d, J=8.5 Hz), 4.30 (2H, q, J=7.0Hz), 4.20-3.96 (4H, m), 3.11 (2H, t, J=6.5 Hz), 2.30 (3H, s), 1.93-1.79(1H, m), 1.30 (3H, t, J=7.0 Hz), 0.90 (3H, t, J=7.0 Hz), 0.90 (6H, d,J=7.0 Hz).

EXAMPLE 17(7)

Ethyl2′-(4-(N²-benzyloxycarbonylamidino)phenylaminomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.59 (Chloroform:Ethyl acetate=1:1); NMR (d₆-DMSO): δ 9.4-8.4(2H, broad), 8.69 (1H, brt, J=6.0 Hz), 8.33 (1H, d, J=2.0 Hz), 8.07 (1H,dd, J=8.0 Hz, 2.0 Hz), 7.73 (2H, d, J=9.0 Hz), 7.50 (1H, d, J=8.0 Hz),7.40-7.24 (8H, m), 7.04 (1H, d, J=7.0 Hz), 6.87 (1H, brt, J=6.0 Hz),6.43 (2H, d, J=9.0 Hz), 5.05 (2H, s), 4.10-3.93 (2H, m), 4.02 (2H, q,J=7.0 Hz), 3.10 (2H, t, J=6.5 Hz), 1.92-1.78 (1H, m), 0.89 (6H, d, J=6.5Hz), 0.89 (3H, t, J=7.0 Hz).

EXAMPLE 17(8)

Ethyl2′-(4-(N²-t-butoxycarbonyloxyamidino)phenylaminomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.68 (Chloroform:Ethyl acetate=1:1); NMR (d₆-DMSO): δ 8.69 (1H,brt, J=6.0 Hz), 8.33 (1H, d, J=2.0 Hz), 8.07(1H, dd, J=8.0 Hz, 2.0 Hz),7.50 (1H, d, J=8.0 Hz), 7.39-7.23 (5H, m), 7.04 (1H, dd, J=7.5 Hz, 1.5Hz), 6.53 (1H, brt, J=6.0 Hz), 6.41 (2H, d, J=9.0 Hz), 6.34 (2H, brs),4.10-3.85 (4H, m), 3.11 (2H, t, J=6.5 Hz), 1.92-1.79 (1H, m), 1.44 (9H,s), 0.89 (3H, t, J=7.0 Hz), 0.89 (6H, d, J=6.5 Hz).

EXAMPLE 17(9)

Ethyl2′-(4-(N²-t-butoxycarbonylamidino)phenoxymethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.36 (Hexane:Ethyl acetate=1:1); NMR (CDCl₃): δ 9.8-8.8 (1H,broad), 8.28 (1H, d, J=2.0 Hz), 7.91 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.71(2H, d, J=9.0 Hz), 7.53 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.41 (1H, td, J=7.5Hz, 1.5 Hz), 7.37 (1H, d, J=8.0 Hz), 7.36 (1H, td, J=7.5 Hz, 1.5 Hz),7.14 (1H, dd, J=7.5 Hz, 1.5 Hz), 6.77 (2H, d, J=9.0 Hz), 6.29 (1H, brt,J=6.5 Hz), 4.81 (2H, s), 4.06 (2H, q, J=7.0 Hz), 3.31 (2H, t, J=6.5 Hz),1.99-1.87 (1H, m), 1.54 (9H, s), 0.99 (6H, d, J=7.0 Hz), 0.96 (3H, t,J=7.0 Hz).

EXAMPLE 17(10)

Ethyl2′-(4-(N²-t-butoxycarbonylamidino)phenylthiomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.40 (Hexane:Ethyl acetate=1:1); NMR (CDCl₃): δ 8.26 (1H, d,J=1.8 Hz), 7.81 (1H, dd, J=1.8, 8.0 Hz), 7.56 (2H, d, J=9.0 Hz), 7.42(1H, dd, J=1.8, 8.0 Hz), 7.32 (1H, dt, J=1.8, 8.0 Hz), 7.27 (1H, dt,J=1.8, 8.0 Hz), 7.23 (1H, d, J=8.0 Hz), 7.06 (1H, dd, J=1.8, 8.0 Hz),7.02 (2H, d, J=9.0 Hz), 6.46 (1H, br.s), 4.06 (2H, q, J=7.4 Hz), 3.94(1H, d, J=13.2 Hz), 3.86 (1H, d, J=13.2 Hz), 3.29 (2H, t, J=6.6 Hz),1.91 (1H,m), 1.53 (9H, s), 0.97 (6H, d, J=6.6 Hz), 0.96 (3H, t, J=7.4Hz).

EXAMPLE 18

Ethyl2′-(4-(N²-t-butoxycarbonyloxyamidino)phenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

4′-((2-methylpropyl)carbamoyl)-2′-ethoxycarbonyl-2-biphenyl carboxylicacid (1.0 g) which was prepared by the same procedure as a series ofreaction of Reference Example 4→Reference Example 5, using ethyl2-trifluoromethylsulfonyloxy-5-((2-methylpropyl)carbamoyl)benzoate, wasdissolved into ethyl acetate (20 ml). Thionyl chloride (0.22 ml) wasdropped into the above solution. The mixture was stirred for 15 minutesat 50° C. The reaction mixture was cooled to room temperature, andconcentrated. A solution of the prepared acyl chloride compound inmethylene chloride (10 ml) and triethylamine (0.57 ml) were added to asolution of 4-(N²-t-butoxycarbonyloxyamidino)aniline in methylenechloride (10 ml) at 0° C. The mixture was stirred for 1 hour at roomtemperature. The reaction mixture was diluted with ethyl acetate (150ml), and washed with a saturated aqueous solution of sodium chloride (75ml, 2 times). The organic layer was dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by columnchromatography on silica gel (methylene chloride:methanol=100:1) to givethe present compound (1.56 g) having the following physical data.

TLC: Rf 0.62 (Chloroform:Methanol=10:1).

EXAMPLE 18(1)-EXAMPLE 18(10)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 18, using a corresponding derivative instead ofthe starting compound in Example 18.

EXAMPLE 18(1)

Ethyl2′-(4-(N²-ethoxycarbonylamidino)phenylcarbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.66 (Chloroform:Methanol:Water=9:1:0.1); NMR (d₆-DMSO): δ 10.27(1H, s), 9.3-8.7 (2H, broad), 7.89 (2H, d, J=9.0 Hz), 7.77 (1H, dd,J=7.5 Hz, 1.5 Hz), 7.70-7.48 (6H, m), 7.42 (1H, td, J=7.5 Hz, 1.5 Hz),7.34-7.24 (2H, m), 4.04 (2H, q, J=7.0 Hz), 3.96 (2H, q, J=7.0 Hz), 1.20(3H, t, J=7.0 Hz), 0.88 (3H, t, J=7.0 Hz).

EXAMPLE 18(2)

Ethyl2′-(4-(N²-t-butoxycarbonyloxyamidino)phenylcarbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.46 (Chloroform:Ethyl acetate=1:1); NMR (CDCl₃): δ 8.67 (1H,brs), 7.82-7.76 (2H, m), 7.53-7.35 (6H, m), 7.27-7.22 (3H, m), 7.13-7.09(1H, m), 5.01 (2H, brs), 4.30-4.22 (2H, m), 1.54 (9H, s), 1.20 (3H, t,J=7.0 Hz).

EXAMPLE 18(3)

Benzyl2′-(4-(N²-t-butoxycarbonyloxyamidino)phenylcarbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.77 (Hexane:Ethyl acetate=1:2); NMR (CDCl₃): δ 8.40 (1H, brs),7.82 (1H, dd, J=1.0, 8.0 Hz), 7.72 (1H, dd, J=1.0, 8.0 Hz), 7.51-7.30(8H, m), 7.25-7.17 (2H, m), 7.10 (2H, brd, J=8.5 Hz), 5.22 (2H, d, J=12Hz), 4.95 (2H, brs), 1.57 (9H, s).

EXAMPLE 18(4)

Ethyl2′-(4-(N²-ethoxycarbonylamidino)phenyloarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.62 (Chloroform:Methanol=10:1); NMR (d₆-DMSO): δ 10.39 (1H, s),9.2-8.8 (2H, br), 8.65 (1H, t, J=7.0 Hz), 8.23 (1H, d, J=2.0 Hz), 8.01(1H, dd, J=2.0, 8.0 Hz), 7.89 (2H, d, J=8.8 Hz), 7.8-7.4 (5H, m), 7.39(1H, d, J=8.0 Hz), 7.29 (1H, dd, J=2.0, 7.0 Hz), 4.05 (2H, q, J=7.2 Hz),3.99 (2H, q, J=7.2 Hz), 3.08 (2H, t, J=7.0 Hz), 1.84 (1H, like septet,J=7.0H), 1.20 (3H, t, J=7.2 Hz), 0.89 (3H, t, J=7.2 Hz), 0.88 (6H, d,J=7.0 Hz).

EXAMPLE 18(5)

Ethyl2′-(4-(N²-ethoxycarbonylamidino)phenyloarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylatemethanesulfonate

TLC: Rf 0.62 (Chloroform:Methanol=10:1); NMR (d₆-DMSO): δ 12.32 (1H,br), 11.12 (1H, br.s), 10.63 (1H, s), 10.43 (1H, br.s), 8.68 (1H, br.t,J=6.4 Hz), 8.23 (1H, d, J=1.6 Hz), 8.03 (1H, dd, J=1.6, 7.9 Hz), 7.74(4H, like s), 7.8-7.6 (1H, m), 7.7-7.5 (2H, m), 7.41 (1H, d, J=7.8 Hz),7.31 (1H, dd, J=1.6, 7.8 Hz), 4.33 (2H, q, J=6.8 Hz), 3.98 (2H, q, J=6.8Hz), 3.09 (2H, t, J=6.4 Hz), 2.37 (3H, s), 1.84 (1H, like septet, J=6.4Hz), 1.31 (3H, t, J=6.8 Hz), 0.89 (3H, t, J=6.8 Hz), 0.88 (6H, d, J=6.4Hz).

EXAMPLE 18(6)

Ethyl2′-(4-(N²-(2-propenyloxycarbonyl)amidino)phenylcarbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.69 (Chloroform:Methanol:Water=9:1:0.1); NMR (CDCl₃): δ 8.95(1H, s), 7.80 (2H, d, J=9.0 Hz), 7.76 (1H, m), 7.34-7.51 (4H, m), 7.33(2H, d, J=9.0 Hz), 7.23 (1H, m), 7.12 (1H, m), 5.97 (1H, m), 5.22-5.42(2H, m), 4.61-4.68 (2H, m), 4.28 (2H, q, J=7.2 Hz), 1.23 (3H, t, J=7.2Hz).

EXAMPLE 18(7)

Benzyl2′-(4-(N²-ethoxycarbonylamidino)phenylcarbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.75 (Chloroform:Methanol=10:1); NMR (CDCl₃): δ 10.0-9.0 (1H,br), 8.5 (1H, s), 7.83 (1H, dd, J=1.6, 7.4 Hz), 7.8-7.6 (3H, m), 7.6-7.3(6H, m), 7.3-7.0 (7H, m), 7.0-6.2 (1H, br), 5.24 (1H, d, J=14.6 Hz),5.18 (1H, d, J=14.6 Hz), 4.19 (2H, q, J=7.4 Hz), 1.33 (3H, t, J=7.4 Hz).

EXAMPLE 18(8)

Benzyl2-(3-(4-(N²-benzyloxycarbonylamidino)phenylcarbamoyl)-5-methoxybenzofuran-2-yl)benzoate

TLC: Rf 0.45 (Hexane:Ethyl acetate=1:1); NMR (d₆-DMSO): δ 10.30 (1H, s),9.3-8.9 (2H, broad), 7.96 (2H, d, J=9.0 Hz), 7.91 (1H, dd, J=7.5 Hz, 2.0Hz), 7.76-7.70 (4H, m), 7.64 (1H, td, J=7.5 Hz, 2.0 Hz), 7.53 (1H, d,J=9.0 Hz), 7.41-7.29 (5H, m), 7.25 (1H, d, J=2.0 Hz), 7.24-7.18 (3H, m),7.16-7.13 (2H, m), 7.02 (1H, dd, J=9.0 Hz, 2.0 Hz), 5.10 (4H, s), 3.83(3H, s).

EXAMPLE 18(9)

Benzyl2′-(6-(N²-t-butoxycarbonylamidino)pyridin-3-ylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.49 (Chloroform:Methanol=10:1); NMR (CDCl₃): δ 9.25 (1H, br s),8.69 (1H, s), 8.28 (1H, d, J=1.6 Hz), 8.23 (1H, d, 6.2 Hz), 8.21 (1H,s), 8.10 (1H, br s), 7.81 (1H, dd, J=1.6, 7.6 Hz), 7.70-7.71 (2H, m),7.58-7.42 (2H, m), 7.40-7.20 (6H, m), 7.09-7.04 (2H, m), 6.25 (1H, t,J=5.8 Hz), 5.29 (1H, d, J=11.6 Hz), 5.17 (1H, d, J=11.6 Hz), 3.26 (2H,t, J=6.2 Hz), 1.88 (1H, septet, J=6.2 Hz), 1.54 (9H, s), 0.96 (6H, d,J=6.2 Hz).

EXAMPLE 18(10)

Benzyl2′-(6-(N²-t-butoxycarbonylamidino)pyridin-3-ylcarbamoyl)-4′-methoxy-4-((1,2,2-trimethylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC: Rf 0.45 (Chloroform:Methanol:Water=9:1:0.1); NMR (CDCl₃): δ 9.3-9.2(1H, broad), 8.77 and 8.73 (1H, s), 8.28-8.20 (2H, m), 8.20-8.08 (1H,broad), 7.81-7.70 (2H, m), 7.38-7.20 (7H, m), 6.99-6.92 (2H, m), 5.91(1H, d, J=9.5 Hz), 5.31-5.09 (2H, m), 4.08 (1H, dq, J=9.5 Hz, 7.0 Hz),3.90 (3H, s), 1.55 (9H, s), 1.14 (3H, d, J=7.0 Hz), 0.95 (9H, s).

EXAMPLE 19-EXAMPLE 19(182)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 4, Example 2, Example 11 or Reference Example 8,using the compound prepared in Example 7-Example 7(83), Example7(86)-Example 7(98), Example 8-Example 8(6), Example 9-Example 9-(31),Example 12-Example 12(3), Example 13, Example 14-Example 14(2), Example15-Example 15(1), Example 16, Example 17-Example 17(5),Example17(7)-Example 17(8), Example 18, Example 18(2)-Example 18(3), Example18(7), Example 7(99)-Example 7(113), Example 8(7), Example 17(9),Example 18(8)-Example 18(9), Example 7(114)-Example 7(115), Example17(10) and Example 18(10).

EXAMPLE 19

2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC: Rf 0.16 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.39(1H, s), 9.14 (2H, s), 8.79 (2H, s), 7.82 (1H, dd, J=1.4,7.6 Hz), 7.73(2H, d, J=9.0 Hz), 7.64-7.69 (3H, m), 7.48-7.56 (3H, m), 7.40 (1H, dt,J=1.4,7.6 Hz), 7.23-7.28 (2H, m), 2.35 (3H, s).

EXAMPLE 19(1)

2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxylic acid hydrochloride

TLC: Rf 0.12 (Chloroform:Methanol:Acetic acid 10:2:1); NMR (d₆-DMSO): δ13.2-12.2 (1H, broad), 10.46 (1H, s), 9.32 (2H, s), 9.16 (2H, s),7.84-7.77 (3H, m), 7.72-7.64 (3H, m), 7.60-7.37 (4H, m), 7.28-7.20 (2H,m).

EXAMPLE 19(2)

3-(4-amidinophenylcarbamoyl)-4-biphenylcarboxylic acid

TLC: Rf 0.31 (Ethyl acetate:Acetic acid:Water=6:1:1); NMR (d₆-DMSO+1drop of MeSO₃H): δ 10.90 (1H, s), 9.20 (2H, s), 9.02 (2H, s), 8.04-7.64(9H, m), 7.60-7.38 (3H, m).

EXAMPLE 19(3)

4-(4-amidinophenylcarbamoyl)-3-biphenylcarboxylic acid

TLC: Rf 0.35 (Ethyl acetate:Acetic acid:Water=6:1:1); NMR (d₆-DMSO+1drop of MeSO₃H): δ 11.59 (1H, s), 10.05 (2H, s), 9.05 (2H, s), 8.10 (1H,d, J=2 Hz), 8.00-7.62 (8H, m), 7.58-7.38 (3H, m).

EXAMPLE 19(4)

3′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC: Rf 0.25 (Ethyl acetate:Acetic acid:Water=6:1:0.5); NMR (d₆-DMSO): δ13.0-12.7 (1H, broad), 10.71 (1H, s), 9.23 (2H, s), 8.96 (2H, s),8.06-7.96 (4H, m), 7.90-7.78 (3H, m), 7.68-7.43 (5H, m), 2.36 (3H, s).

EXAMPLE 19(5)

2,3-dihydro-2,2-dimethyl-5-(2-(4-amidinophenylcarbamoyl)phenyl)-6-benzofurancarboxylicacid methanesulfonate

TLC: Rf 0.40 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.3 (1H, broad), 10.28 (1H, s), 9.16 (2H, s), 8.90 (2H, s), 7.75(2H, d, J=9 Hz), 7.66 (2H, d, J=9 Hz), 7.62 (1H, dd, J=7 Hz, 2 Hz),7.57-7.41 (2H, m), 7.22 (1H, dd, J=7 Hz, 2 Hz), 7.05 (1H, s), 7.04 (1H,s), 3.00 (2H, s), 2.36 (3H, s), 1.40 (6H, s).

EXAMPLE 19(6)

2′-(4-amidinophenylcarbamoyl)-3-biphenylcarboxylic acid methanesulfonate

TLC: Rf 0.34 (Chloroform:Methanol:Acetic acid=10:2:1) NMR (d₆-DMSO): δ13.3-12.7 (1H, broad), 10.71 (1H, s), 9.19 (2H, s), 8.98 (2H, s), 8.03(1H, s), 7.88 (1H, d, J=8 Hz), 7.80-7.43 (10H, m), 2.38 (3H, s).

EXAMPLE 19(7)

2′-(4-amidinophenylcarbamoyl)-2,3-biphenyldicarboxylic acid

TLC: Rf 0.27 (Chloroform:Methanol:Water=6:4:1); NMR (d₆-DMSO): δ14.0-12.0(1H, broad), 10.81 (1H, brs), 9.24(2H, brs), 8.20 (2H, brs),7.84-7.24 (11H, m).

EXAMPLE 19(8)

2′-(4-amidinophenylcarbamoyl)-6-methyl-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.12 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.2-12.2 (1H, broad), 10.42 (1H, s), 9.15 (2H, brs), 8.91 (2H, brs),7.75-7.50 (8H, m), 7.39 (1H, d, J=8 Hz), 7.30 (1H, t, J=8 Hz), 7.10 (1H,dd, J=8 Hz, 2 Hz), 2.35 (3H, s), 1.92 (3H, s).

EXAMPLE 19(9)

2′-(4-amidinophenylcarbamoyl)-5-methoxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.29 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.40(1H, s), 9.15 (2H, s), 8.82 (2H, s), 7.82 (1H, d, J=8.8 Hz), 7.73 (2H,d, J=9.0 Hz), 7.68 (2H, d, J=9.0 Hz), 7.66 (1H, d, J=8.8 Hz), 7.44-7.58(2H, m), 7.26 (1H, d, J=7.8 Hz), 6.92 (1H, dd, J=2.2,8.8 Hz), 6.75 (1H,d, J=2.2 Hz), 3.76 (3H, s), 2.36 (3H, s).

EXAMPLE 19(10)

2′-(4-amidinophenylcarbamoyl)-4-methoxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.31 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.38(1H, s), 9.16 (2H, s), 8.87 (2H, s), 7.75 (2H, d, J=9.0 Hz), 7.69 (2H,d, J=9.0 Hz), 7.63 (1H, d, J=8.0 Hz), 7.53 (1H, t, J=8.0 Hz), 7.48 (1H,t, J=8.0 Hz), 7.32 (1H, d, J=2.2 Hz), 7.23 (1H, d, J=8.0 Hz), 7.17 (1H,d, J=8.6 Hz), 7.08 (1H, dd, J=2.2,8.6 Hz), 3.79 (3H, s), 2.35 (3H, s).

EXAMPLE 19(11)

2′-(4-amidinophenylcarbamoyl)-4-biphenylcarboxylic acid methanesulfonate

TLC: Rf 0.12 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.97 (1H, brs), 10.73 (1H, s), 9.18 (2H, brs), 8.95 (2H, brs), 7.91(2H, d, J=8.5 Hz), 7.80-7.50 (10H, m), 2.34 (3H, s).

EXAMPLE 19(12)

2′-(4-amidinophenylcarbamoyl)-6-methoxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.30 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.34(1H, s), 9.15 (2H, s), 8.83 (2H, s), 7.73 (4H, s), 7.67 (1H, m),7.45-7.54 (2H, m), 7.36-7.38 (2H, m), 7.11-7.16 (2H, m), 3.56 (3H, s),2.34 (3H, s).

EXAMPLE 19(13)

2′-(4-amidinophenylcarbamoyl)-4-hydroxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.1 9 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ10.25 (1H, s), 9.76 (1H, s), 9.15 (2H, s), 8.82 (2H, s), 7.74 (2H, d,J=8.8 Hz), 7.66 (2H, d, J=8.8 Hz), 7.60 (1H, dd, J=2.0,7.6 Hz), 7.50(1H, dt, J=2.0,7.6 Hz), 7.45 (1H, dt, J=2.0,7.6 Hz), 7.21 (1H, dd,J=2.0,7.6 Hz), 7.19 (1H, d, J=2.4 Hz), 7.03 (1H, d, J=8.2 Hz), 6.87 (1H,dd, J=2.4,8.2 Hz), 2.35 (3H, s).

EXAMPLE 19(14)

2′-(4-amidinophenylcarbamoyl)-5-hydroxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.19 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.34(1H, s), 10.16 (1H, s), 9.14 (2H, s), 8.78 (2H, s), 7.73 (2H, d, J=8.8Hz), 7.72 (1H, d, J=8.6 Hz), 7.67 (2H, d, J=8.8 Hz), 7.63 (1H, dd,J=2.4,7.2 Hz), 7.47-7.53 (2H, m), 7.20 (1H, dd, J=2.4,7.2 Hz), 6.75 (1H,dd, J=2.4,8.6 Hz), 6.56 (1H, d, J=2.4 Hz), 2.34 (3H, s).

EXAMPLE 19(15)

2′-(4-amidinophenylcarbamoyl)-5-methyl-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.15 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.37 (1H, s), 9.13 (2H, brs), 8.80 (2H, brs), 7.72 (2H, d, J=8.0 Hz),7.66 (2H, d, J=8.0 Hz), 7.70-7.60 (2H, m), 7.50 (1H, dt, J=1.5, 8.0 Hz),7.45 (1H, dt, J=1.5, 8.0 Hz), 7.20 (1H, dd, J=2.0, 7.5 Hz), 7.16 (1H,dd, J=2.0, 8.0 Hz), 7.01 (1H, s), 5.00-3.60 (1H, m), 2.29 (3H, s), 2.27(3H, s).

EXAMPLE 19(16)

2′-(4-amidinophenylcarbamoyl)-4-methyl-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.14 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.42 (1H, s), 9.14 (2H, brs), 8.81 (2H, brs), 7.70 (2H, d, J=8.0 Hz),7.65 (2H, d, J=8.0 Hz), 7.66-7.60 (1H, m), 7.61 (1H, s), 7.50 (1H, brt,J=8.0 Hz), 7.45 (1H, brt, J=8.0 Hz), 7.30 (1H, d, J=7.5 Hz), 7.20 (1H,d, J=7.5 Hz), 7.10(1H, d, J=8.0 Hz), 4.20-3.50 (1H, m), 2.31 (6H, s).

EXAMPLE 19(17)

2′-(4-amidinophenylcarbamoyl)-3-hydroxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.42 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.36(1H, s), 9.16 (2H, s), 8.81 (2H, s), 7.74 (2H, d, J=8.8 Hz), 7.65 (2H,d, J=8.8 Hz), 7.50-7.65 (3H, m), 7.19-7.30 (2H, m), 6.86 (1H, d, J=8.4Hz), 6.61 (1H, d, J=7.0 Hz), 2.33 (3H, s).

EXAMPLE 19(18)

2′-(4-amidinophenylcarbamoyl)-4′-methyl-5-chloro-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.19 (Chloroform:Methanol:Acetic acid=4:1:0.1); NMR (d₆-DMSO): δ13.2-12.0 (1H, br), 10.50 (1H, s), 9.17 (2H, s), 8.85 (2H, s), 7.82 (1H,d, J=8.4 Hz), 7.74 (4H, s), 7.5-7.3 (3H, m), 7.26 (1H, d, J=1.8 Hz),7.18 (1H, d, J=7.8 Hz), 2.44 (3H, s), 2.35 (3H, s).

EXAMPLE 19(19)

2′-(4-amidinophenylcarbamoyl)-3-methoxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.28 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.32(1H, br.s), 9.16 (2H, s), 8.85 (2H, s), 7.75 (2H, d, J=8.8 Hz), 7.67(1H, m), 7.64 (2H, d, J=8.8 Hz), 7.53-7.57 (2H, m), 7.29-7.37 (2H, m),7.05 (1H, d, J=8.4 Hz), 6.79 (1H, d, J=7.6 Hz), 3.83 (3H, s), 2.34 (3H,s).

EXAMPLE 19(20)

2′-(4-amidinophenylcarbamoyl)-4′-methyl-4-methoxy-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.24 (Chloroform:Methanol:Acetic acid=4:1:0.1); NMR (d₆-DMSO): δ13.4-12.0 (1H, br), 10.36 (1H, s), 9.14 (2H, s), 8.83 (2H, s), 7.7-7.6(3H, m), 7.44 (1H, s), 7.4-7.2 (2H, m), 7.2-7.0 (4H, m), 3.78 (3H, s),2.42 (3H, s), 2.37 (3H, s).

EXAMPLE 19(21)

2-(2-(4-amidinophenylcarbamoyl)phenyl)-1-naphthalenecarboxylic acidmethanesulfonate

TLC: Rf 0.40 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.50(1H, br.s), 9.12 (2H, s), 8.83 (2H, s), 7.93-8.00 (3H, m), 7.58-7.79(9H, m), 7.42 (1H, m), 7.37 (1H, d, J=8.4 Hz), 2.35 (3H, s).

EXAMPLE 19(22)

2′-(4-amidinophenylcarbamoyl)-3-methyl-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.19 (Chloroform:Methanol:Acetic acid=4:1:0.1); NMR (d₆-DMSO): δ13.7-12.7 (1H, br), 10.29 (1H, s), 9.16 (2H, s), 8.83 (2H, s), 7.74 (2H,d, J=8.8 Hz), 7.59 (2H, d, J=8.8 Hz), 7.8-7.6 (1H, m), 7.6-7.5 (2H, m),7.4-7.2 (1H, m), 7.25 (2H, d, J=7 Hz), 7.03 (1H, dd, J=7.4, 2 Hz), 2.37(3H, s), 2.34 (3H, s).

EXAMPLE 19(23)

3-(2-(4-amidinophenylcarbamoyl)phenyl)-7-methoxy-2-naphthalenecarboxylicacid methanesulfonate

TLC: Rf 0.61 (Ethyl acetate: Acetic acid:Water=3:1:0.5); NMR (d₆-DMSO):δ 12.84 (1H, br.s), 10.40 (1H, s), 9.09 (2H, br.s), 8.78 (2H, br.s),8.35 (1H, s), 7.84 (1H, d, J=9.4 Hz), 7.7-7.4 (9H, m), 7.34 (1H, dd,J=7.2, 1.4 Hz), 7.26 (1H, dd, J=9.4, 2.4 Hz), 3.87 (3H , s), 2.32 (3H,s).

EXAMPLE 19(24)

3-(2-(4-amidinophenylcarbamoyl)phenyl)-5-methoxy-2-naphthalenecarboxylicacid methanesulfonate

TLC: Rf 0.29 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ12.88 (1H, br.s), 10.49 (1H, s), 9.10 (2H, br.s), 8.79 (2H, br.s), 8.40(1H, s), 7.94 (1H, s), 7.8-7.4 (9H, m), 7.34 (1H, dd, J=2.0, 6.8 Hz),7.07 (1H, d, J=7.4 Hz), 3.91 (3H, s), 2.32 (3H, s).

EXAMPLE 19(25)

2′-(4-amidinophenylcarbamoyl)-2,4-biphenyldicarboxylic acidmethanesulfonate

TLC: Rf 0.22 (Chloroform:Methanol:Water=6:4:1); NMR (d₆-DMSO): δ 13.02(1H, br.s), 10.54 (1H, s), 9.16 (2H, s), 8.89 (2H, s), 8.38 (1H, d,J=2.0 Hz), 8.05 (1H, dd, J=2.0,7.8 Hz), 7.74 (4H, s), 7.73 (1H, dd,J=2.6,7.8 Hz), 7.53-7.60 (2H, m), 7.37 (1H, d, J=7.8 Hz), 7.29 (1H, dd,J=2.6,7.8 Hz), 2.38 (3H, s).

EXAMPLE 19(26)

2′-(4-amidinophenylcarbamoyl)-4-dimethylcarbamoyl-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.46 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.43(1H, s), 9.16 (2H, s), 8.88 (2H, s), 7.67-7.80 (6H, m), 7.52-7.59 (3H,m), 7.31 (2H, d, J=7.8 Hz), 2.98 (3H, br.s), 2.85 (3H, br.s), 2.37 (3H,s).

EXAMPLE 19(27)

3-(2-(4-amidinophenylcarbamoyl)phenyl)-6-methoxy-2-naphthalenecarboxylicacid methanesulfonate

TLC: Rf 0.51 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ13.0-12.0 (1H, br), 11.5-10.5 (1H, br), 9.05 (2H, br.s), 8.85 (2H,br.s), 8.29 (1H, s), 7.93 (1H, d, J=8.8 Hz), 7.7-7.5 (5H, m), 7.6-7.4(3H, m), 7.4-7.1 (3H, m), 3.84 (3H, s), 2.30 (3H, s).

EXAMPLE 19(28)

2′-(4-amidinophenylcarbamoyl)-4-methylcarbamoyl-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.27 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.49(1H, s), 9.16 (2H, s), 8.89 (2H, s), 8.62 (1H, br.q, J=4.6 Hz), 8.30(1H, d, J=1.8 Hz), 7.96 (1H, dd, J=1.8,8.2 Hz), 7.76 (2H, d, J=9.0 Hz),7.71 (2H, d, J=9.0 Hz), 7.70 (1H, dd, J=2.0,7.6 Hz), 7.52-7.58 (2H, m),7.33 (1H, d, J=8.2 Hz), 7.28 (1H, dd, J=2.0,7.6 Hz), 2.79 (3H, br.d,J=4.6 Hz), 2.39 (3H, s).

EXAMPLE 19(29)

3-(2-(4-amidinophenylcarbamoyl)phenyl)-8-methoxy-2-naphthalenecarboxylicacid methanesulfonate

TLC: Rf 0.26 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ12.76 (1H, br.s), 10.45 (1H, s), 9.09 (2H, br.s), 8.80 (2H, br.s), 8.68(1H, s), 7.8-7.5 (10H, m), 7.35 (1H, m), 7.04 (1H, m), 4.00 (3H, s),2.33 (3H, s).

EXAMPLE 19(30)

2′-(4-amidinophenylcarbamoyl)-3,4-dimethoxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.16 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.7-13.2 (1H, broad), 10.30 (1H, s), 9.16 (2H, brs), 8.89 (2H, brs),7.76 (2H, d, J=9.0 Hz), 7.69-7.62 (3H, m), 7.58-7.46 (2H, m), 7.33-7.27(1H, m), 7.07 (1H, d, J=8.5 Hz), 6.92 (1H, d, J=8.5 Hz), 3.79 (3H, s),3.77 (3H, s), 2.35 (3H, s).

EXAMPLE 19(31)

6-(2-(4-amidinophenylcarbamoyl)phenyl)-1,2-methylenedioxybenzen-5-carboxylicacid methanesulfonate

TLC: Rf 0.22 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.8-12.2 (1H, broad), 10.39 (1H, s), 9.16 (2H, brs), 8.88 (2H, brs),7.76 (2H, d, J=9.0 Hz), 7.70 (2H, d, J=9.0 Hz), 7.65-7.60 (1H, m),7.56-7.42 (2H, m), 7.30 (1H, s), 7.24-7.19 (1H, m), 6.75 (1H, s), 6.10(2H, s), 2.34 (3H, s).

EXAMPLE 19(32)

2′-(4-amidinophenylcarbamoyl)-4′-nitro-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.21 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.5 (1H, broad), 10.77 (1H, s), 9.16 (2H, brs), 8.88 (2H, brs),8.49 (1H, d, J=2.5 Hz), 8.39 (1H, dd, J=8.5 Hz, 2.5 Hz), 7.91 (1H, dd,J=8.0 Hz, 1.5 Hz), 7.76 (2H, d, J=9.0 Hz), 7.69 (2H, d, J=9.0 Hz), 7.59(1H, td, J=8.0 Hz, 1.5 Hz), 7.58 (1H, d, J=8.5 Hz), 7.48 (1H, d, J=8.0Hz, 1.5 Hz), 7.28 (1H, dd, J=8.0 Hz, 1.5 Hz), 2.34 (3H, s).

EXAMPLE 19(33)

2′-(4-amidinophenylcarbamoyl)-4-((carboxymethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.28 (Chloroform:Methanol:Water=6:4:1); NMR (d₆-DMSO): δ 10.54(1H, s), 9.22 (2H, s), 9.07 (1H, br.t, J=5.6 Hz), 9.01 (2H, s), 8.35(1H, d, J=1.2 Hz), 8.01 (1H, dd, J=1.2,7.6 Hz), 7.70-7.75 (5H, m),7.50-7.62 (2H, m), 7.36 (1H, d, J=7.6 Hz), 7.30 (1H, d, J=7.6 Hz), 3.94(2H, d, J=5.6 Hz), 2.42 (3H, s).

EXAMPLE 19(34)

2′-(4-amidinophenylcarbamoyl)-4-((1-carboxy-2-phenylethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.20 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.53(1H, s), 9.17 (2H, s), 8.95 (1H, d, J=5.0 Hz), 8.92 (2H, s), 8.28 (1H,d, J=1.6 Hz), 7.92 (1H, dd, J=1.6,8.0 Hz), 7.69-7.74 (5H, m), 7.53-7.58(2H, m), 7.17-7.35 (7H, m), 4.64 (1H, m), 3.01-3.26 (2H, m), 2.39 (3H,s).

EXAMPLE 19(35)

2′-(4-amidinophenylcarbamoyl)-2-biphenylphosphoric acid methanesulfonate

TLC: Rf 0.10 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ11.37 (1H, s), 9.10 (2H, brs), 8.85 (2H, brs), 7.87-7.74 (1H, m), 7.65(2H, d, J=9.0 Hz), 7.59 (2H, d, J=9.0 Hz), 7.60-7.30 (5H, m), 7.26 (1H,dd, J=6.0 Hz, 3.0 Hz), 7.05-6.97 (1H, m), 2.33 (3H, s).

EXAMPLE 19(36)

2′-(4-amidinophenylcarbamoyl)-4-fluoro-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.45 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.45(1H, s), 9.16 (2H, s), 8.84 (2H, s), 7.73 (4H, s), 7.67 (1H, dd,J=2.6,8.0 Hz), 7.50-7.61 (3H, m), 7.39 (1H, dt, J=2.6,8.0 Hz), 7.25-7.32(2H, m), 2.36 (3H, s).

EXAMPLE 19(37)

2′-(4-amidinophenylcarbamoyl)-4-benzylcarbamoyl-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.70 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.54(1H, s), 9.26 (1H, br.t, J=5.8 Hz), 9.17 (2H, s), 8.90 (2H, s), 8.37(1H, d, J=1.8 Hz), 8.03 (1H, dd, J=1.8,8.0 Hz), 7.74 (4H, s), 7.71 (1H,dd, J=1.8,8.0 Hz), 7.53-7.59 (2H, m), 7.24-7.37 (7H, m), 4.48 (2H, d,J=5.8 Hz), 2.34 (3H, s).

EXAMPLE 19(38)

2′-(4-amidinophenylcarbamoyl)-4-phenylethylcarbamoyl-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.56 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.52(1H, s), 9.15 (2H, s), 8.83 (2H, s), 8.77 (1H, br.t, J=5.8 Hz), 8.30(1H, d, J=1.8 Hz), 7.95 (1H, dd, J=1.8,8.0 Hz), 7.73 (4H, s), 7.70 (1H,dd, J=1.8,8.0 Hz), 7.52-7.59 (2H, m), 7.19-7.35 (7H, m), 3.50 (2H, m),2.85 (2H, t, J=7.0 Hz), 2.34 (3H, s).

EXAMPLE 19(39)

2′-(4-amidinophenylcarbamoyl)-4-(2-methoxycarbonylethyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.24 (Chloroform:Methanol=4:1); NMR (d₆-DMSO): δ 13.0-12.5 (1H,br), 10.41 (1H, s), 9.14 (2H, s), 8.82 (2H, s), 7.8-7.6 (6H, m), 7.6-7.4(2H, m), 7.38-7.34 (1H, m), 7.25-7.21 (1H, m), 7.14 (1H, d, J=7.8 Hz),3.56 (3H, s), 2.89 (2H, t, J=6.8 Hz), 2.64 (2H, t, J=6.8 Hz), 2.34 (3H,s).

EXAMPLE 19(40)

2′-(4-amidinophenylcarbamoyl)-4-(2-methoxyethoxy)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.42 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.8-12.5 (1H, br), 10.37 (1H, s), 9.13 (2H, br.s), 8.79 (2H, br.s),7.80-7.55 (5H, m), 7.55-7.40 (2H, s), 7.30 (1H, d, J=2.4 Hz), 7.80-7.00(3H, m), 4.11 (2H, t, J=4.4 Hz), 3.64 (2H, t, J=4.4 Hz), 3.28 (3H, s),2.31 (3H, s).

EXAMPLE 19(41)

2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.26 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.53(1H, s), 9.15 (2H, s), 8.85 (2H, s), 8.65 (1H, br.t, J=6.8 Hz), 8.31(1H, d, J=1.8 Hz), 7.97 (1H, dd, J=1.8,7.8 Hz), 7.74 (4H, s), 7.70 (1H,dd, J=1.8,7.8 Hz), 7.52-7.59 (2H, m), 7.33 (1H, d, J=7.8 Hz), 7.28 (1H,dd, J=1.8,7.8 Hz), 3.09 (2H, br.t, J=6.8 Hz), 2.35 (3H, s), 1.85 (1H,m), 0.89 (6H, d, J=6.8 Hz).

EXAMPLE 19(42)

2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.61 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.53(1H, s), 9.14 (2H, s), 8.82 (1H, d, J=7.8 Hz), 8.77 (2H, s), 8.31 (1H,d, J=1.6 Hz), 7.99 (1H, dd, J=1.6,8.0 Hz), 7.74 (4H, s), 7.32 (1H, d,J=8.0 Hz), 7.24 (1H, m), 7.13-7.19 (2H, m), 4.31 (1H, t, J=7.8 Hz), 3.89(3H, s), 3.66 (3H, s), 2.32 (3H, s), 2.18 (1H, m), 0.98 (3H, d, J=6.6Hz), 0.94 (3H, d, J=6.6 Hz).

EXAMPLE 19(43)

2′-(4-amidinophenylcarbamoyl)-4-trifluoromethoxy-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.25 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.5(1H, s), 9.15 (2H, brs), 8.84 (2H, brs), 7.74-7.69 (6H, m), 7.59-7.53(3H, m), 7.38 (1H, d, J=8.4 Hz), 7.33-7.28 (1H, m), 2.37 (3H, s).

EXAMPLE 19(44)

2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-((1-methoxycarbonyl-2-methylpropyl)carbamoyl)benzoicacid methanesulfonate

TLC: Rf 0.48 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.78(1H, s), 9.18 (2H, s), 8.89 (1H, d, J=7.6 Hz), 8.87 (2H, s), 8.40 (1H,d, J=1.8 Hz), 8.33 (1H, s), 8.01-8.14 (3H, m), 7.74-7.85 (5H, m),7.64-7.69 (2H, m), 7.46 (1H, d, J=8.0 Hz), 4.34 (1H, t, J=7.6 Hz), 3.68(3H, s), 2.35 (3H, s), 2.23 (1H, m), 1.00 (3H, d, J=7.0 Hz), 0.96 (3H,d, J=7.0 Hz).

EXAMPLE 19(45)

3-(2-(4-amidinophenylcarbamoyl)phenyl)-8-(2-methoxyethoxy)-2-naphthalenecarboxylicacid methanesulfonate

TLC: Rf 0.61 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.1-12.0 (1H, br), 10.44 (1H, s), 9.09(2H, brs), 8.80 (2H, brs), 8.67(1H, s), 7.70 (1H, s), 7.67 (4H, likes), 7.7-7.4 (5H, m), 7.36 (1H, brd,J=7.8 Hz), 7.05 (1H, brd, J=5.4 Hz), 4.4-4.2 (2H, m), 3.9-3.7 (2H, m),3.36 (3H, s), 2.32 (3H, s).

EXAMPLE 19(46)

2′-(4-amidinophenylcarbamoyl)-4-((isopropylcarbonyl)aminomethyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.54 (Chloroform:Methanol:Water=8:2:0.1); NMR (d₆-DMSO): δ 10.5(1H, s), 9.17 (2H, br s), 8.87 (2H, br s), 8.35 (1H, t, J=6.6 Hz),7.78-7.64 (6H, m), 7.55-7.48 (2H, m), 7.36 (1H, dd, J=1.8, 8.0 Hz),7.24-7.16 (2H, m), 4.30 (2H, d, J=6.0 Hz), 2.52-2.41 (1H, m ) 2.36 (3H,s), 1.04 (6H, d, J=7.0 Hz).

EXAMPLE 19(47)

2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-((2-methylpropyl)carbamoyl)benzoicacid methanesulfonate

TLC: Rf 0.74 (Chloroform:Methanol:Water 7:3:0.3); NMR (d₆-DMSO): δ 10.76(1H, s), 9.18 (2H, s), 8.86-8.93 (3H, m), 8.68 (1H, br.t, J=6.6 Hz),8.36 (1H, s), 8.32 (1H, s), 8.00-8.14 (3H, m), 7.79 (4H, s), 7.63-7.68(2H, m), 7.44 (1H, d, J=8.0 Hz), 3.11 (2H, br.t, J=6.6 Hz), 2.36 (3H,s), 1.88 (1H, m), 0.91 (6H, d, J=6.6 Hz).

EXAMPLE 19(48)

2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.62 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.51(1H, s), 9.14 (2H, s), 8.83 (2H, s), 8.63 (1H, br.t, J=6.6 Hz), 8.28(1H, d, J=2.0 Hz), 7.95 (1H, dd, J=2.0,8.0 Hz), 7.74 (4H, s), 7.30 (1H,d, J=8.0 Hz), 7.24 (1H, d, J=2.0 Hz), 7.21 (1H, d, J=8.0 Hz), 7.14 (1H,dd, J=2.0,8.0 Hz), 3.89 (3H, s), 3.09 (2H, t, J=6.6 Hz), 2.35 (3H, s),1.85 (1H, m), 0.89 (6H, d, J=7.0 Hz).

EXAMPLE 19(49)

2′-(4-amidinophenylcarbamoyl)-4-isopropylcarbamoyl-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.33 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.16 (2H, br s), 8.86 (2H, br s), 8.43 (1H, d, J=7.6 Hz),8.30 (1H, d, J=1.6 Hz), 7.97 (1H, dd, J=1.6, 8.0 Hz), 7.73-7.68 (5H, m),7.59-7.52 (2H, m), 7.34-7.25 (2H, m), 4.20-4.02 (1H, m ), 2.34 (3H, s),1.17 (6H, d, J=6.6 Hz).

EXAMPLE 19(50)

2′-(4-amidinophenylcarbamoyl)-4-((3-methylbutyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.42 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.14 (2H, brs), 8.83 (2H, brs), 8.61 (1H, t, J=6.0 Hz),8.30 (1H, d, J=1.6 Hz), 7.96 (1H, dd, J=1.6, 8.0 Hz), 7.73-7.68 (5H, m),7.62-7.53 (2H, m), 7.35-7.26 (2H, m), 3.34-3.24 (2H, m), 2.37 (3H, s),1.69-1.53 (1H, m), 1.48-1.37 (2H, m), 0.90 (6H, d, J=6.2 Hz).

EXAMPLE 19(51)

2′-(4-amidinophenylcarbamoyl)-4-ethylcarbamoyl-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.10 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.17 (2H, br s), 8.86 (2H, br s), 8.66 (1H, t, J=5.4 Hz),8.30 (1H, d, J=1.8 Hz), 7.97 (1H, dd, J=1.8, 7.6 Hz), 7.73-7.68 (5H, m),7.59-7.52 (2H, m), 7.35-7.26 (2H, m), 3.36-3.23 (2H, m ), 2.36 (3H, s),1.13 (3H, t, J=7.0 Hz).

EXAMPLE 19(52)

2′-(4-amidinophenylcarbamoyl)-4-butylcarbamoyl-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.26 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.16 (2H, br s), 8.85 (2H, br s), 8.63 (1H, t, J=5.4 Hz),8.30 (1H, d, J=1.6 Hz), 7.97 (1H, dd, J=1.6, 8.2 Hz), 7.73-7.68 (5H, m),7.58-7.53 (2H, m), 7.35-7.26 (2H, m), 3.32-3.22 (2H, m ),1.55-1.24 (4H,m), 2.36 (3H, s), 0.90 (3H, t, J=7.2 Hz).

EXAMPLE 19(53)

2′-(4-amidinophenylcarbamoyl)-4′-methyl-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.33 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.51(1H, s), 9.15 (2H, br.s), 8.83 (2H, br.s), 8.63 (1H, t, J=6.2 Hz), 8.29(1H, d, J=1.8 Hz), 7.95 (1H, dd, J=1.8,8.0 Hz), 7.73 (4H, s), 7.51 (1H,s), 7.38 (1H, d, J=8.0 Hz), 7.29 (1H, d, J=8.0 Hz), 7.16 (1H, d, J=8.0Hz), 3.09 (2H, t, J=6.2 Hz), 2.45 (3H, s), 2.36 (3H, s), 1.86 (1H, m),0.89 (6H, d, J=6.6 Hz).

EXAMPLE 19(54)

2′-(4-amidinophenylcarbamoyl)-4-((cyclohexylmethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.40 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.17 (2H, br s), 8.87 (2H, br s), 8.60 (1H, t, J=5.4 Hz),8.30 (1H, d, J=1.6 Hz), 7.97 (1H, dd, J=1.6, 8.0 Hz), 7.74-7.69 (5H, m),7.62-7.50 (2H, m), 7.34-7.26 (2H, m), 3.11 (1H, t, J=5.8 Hz), 2.36 (3H,s), 1.8-1.40 (6H, m), 1.30-0.75 (5H, m).

EXAMPLE 19(55)

2′-(4-amidinophenylcarbamoyl)-4-((5-(t-butoxycarbonylamino)pentyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC: Rf 0.39 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, d, J=5.8 Hz), 9.17 (2H, br s), 8.86 (2H, m), 8.65 (1H, t,J=5.8 Hz), 8.30 (1H, s), 8.00-7.95 (1H, m), 7.74-7.60 (4H, m), 7.60-7.50(2H, m), 7.35-7.25 (2H, m), 6.75 (1H, br s), 3.40-3.20 (2H, m),3.00-2.70 (2H, m), 2.34 (3H, s), 1.60-1.20 (6H, m), 1.36 (9H, s).

EXAMPLE 19(56)

2′-(4-amidinophenylcarbamoyl)-4-((1-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.23 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.18 (2H, br s), 8.89 (2H, br s), 8.36 (1H, d, J=8.2 Hz),8.31 (1H, d, J=1.8 Hz), 7.98 (1H, dd, J=1.8, 8.2 Hz), 7.74-7.69 (4H, m),7.59-7.52 (2H, m), 7.32 (1H, d, J=8.2 Hz), 7.30-7.26 (1H, m), 4.10-3.90(1H, m), 2.37 (3H, s), 1.56-1.48 (2H, m), 1.14 (3H, d, J=6.6 Hz), 0.87(3H, t, J=7.4 Hz.

EXAMPLE 19(57)

2′-(4-amidinophenylcarbamoyl)-4-((tetrahydropyran-4-ylmethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.53 (Chloroform:Methanol:Water=7:3:0.3) NMR (d₆-DMSO): δ13.3-12.5 (1H, broad), 10.54 (1H, s), 9.19 (2H, s), 8.95 (2H, s), 8.69(1H, brt, J=6.0 Hz), 8.30 (1H, d, J=2.0 Hz), 7.97 (1H, dd, J=8.0 Hz, 2.0Hz), 7.73 (4H, s), 7.70 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.62-7.47 (2H, m),7.32 (1H, d, J=8.0 Hz), 7.29-7.24 (1H, m), 3.83 (2H, dd, J=11 Hz, 2.5Hz), 3.25 (2H, brt, J=11 Hz), 3.15 (2H, brt, J=6.0 Hz), 2.34 (3H, s),1.90-1.65 (1H, m), 1.58 (2H, brd, J=13 Hz), 1.30-1.06 (2H, m).

EXAMPLE 19(58)

2′-(4-amidinophenylcarbamoyl)-4-((2-hydroxypropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.38 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.17 (2H, br s), 8.87 (2H, br s), 8.61 (1H, t, J=5.6 Hz),8.32 (1H, d, J=1.8 Hz), 7.99 (1H, dd, J=1.8, 7.6 Hz), 7.73-7.68 (5H, m),7.62-7.52 (2H, m), 7.35-7.26 (2H, m), 4.20-3.60 (1H, br s), 3.90-3.70(1H, m), 3.22 (2H, d, J=5.6 Hz), 2.36 (3H, s), 1.07 (3H, d, J=6.2 Hz).

EXAMPLE 19(59)

2′-(4-amidino-2-hydroxyphenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.16 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.6-13.0 (1H, broad), 10.56 (1H, s), 9.08 (2H, brs), 8.91 (1H, s), 8.81(2H, brs), 8.67 (1H, brt, J=5.5 Hz), 8.35 (1H, d, J=2.0 Hz), 8.20 (1H,d, J=8.5 Hz), 7.95 (1H, dd, J=8.5 Hz, 2.0 Hz), 7.77-7.71 (1H, m),7.58-7.48 (2H, m), 7.28 (1H, d, J=8.5 Hz), 7.20-7.11 (2H, m), 7.08 (1H,d, J=2.0 Hz), 3.06 (2H, brt, J=6.0 Hz), 2.33 (3H, s), 1.93-1.73 (1H, m),0.87 (6H, d, J=6.5 Hz).

EXAMPLE 19(60)

2′-(4-amidinophenylcarbamoyl)-4-(N-methyl-N-(2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.11 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.17 (2H, brs), 8.91 (2H, brs), 7.73-7.40 (9H, m), 7.31(2H, d, J=7.8 Hz), 3.30-2.94 (2H, m, rotamers), 2.94 (3H, s, each ofrotamers), 2.84 (3H, s, each of rotamers), 2.39 (3H, s, each ofrotamers), 2.38 (3H, s, each of rotamers), 0.91 (6H, d, J=6.6 Hz, eachof rotamers), 0.62 (6H, m, each of rotamers).

EXAMPLE 19 (61)

2′-(4-amidinophenylcarbamoyl)-4-((2-methyl-1-(methylaminomethyl)propyl)carbamoyl)-2-biphenylcarboxylic acid dimethanesulfonate

TLC: Rf 0.36 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ13.0-12.0 (1H, br), 10.62 (1H, s), 9.18 (2H, br.s), 8.96 (2H, br.s),8.49 (1H, d, J=8.8 Hz), 8.6-8.3 (2H, br), 8.35 (1H, d, J=1.4 Hz), 8.03(1H, dd, J=1.4, 8.0 Hz), 7.8-7.6 (1H, m), 7.75 (4H, like s), 7.55 (2H,m), 7.35 (1H, d, J=8.0 Hz),7.25 (1H, dd, J=1.4, 6.8 Hz), 4.13 (1H, m),3.3-2.9 (2H, br), 2.53 (3H, br.t, J=5.0 Hz), 2.36 (6H, s), 1.83 (1H, m),0.92 (3H, d, J=6.4 Hz), 0.88 (3H, d, J=6.4 Hz).

EXAMPLE 19(62)

2′-(4-amidinophenylcarbamoyl)-4-((2-hydroxy-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.10 (Chloroform:Methanol:Water=8:2:0.1); NMR (d₆-DMSO): δ 10.5(1H, s), 9.16 (2H, br s), 8.85 (2H, br s), 8.47 (1H, t, J=5.8 Hz), 8.32(1H, d, J=1.8 Hz), 8.01 (1H, dd, J=1.8, 8.0 Hz), 7.74-7.69 (5H, m),7.59-7.53 (2H, m), 7.35-7.26 (2H, m), 3.26 (2H, d, J=5.8 Hz), 2.35 (3H,s), 1.11 (6H, s).

EXAMPLE 19(63)

2′-(4-amidino-2-methylphenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.28 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.5-12.6 (1H, broad), 9.49 (1H, s), 9.18 (2H, brs), 8.94 (2H, brs),8.67 (1H, brt, J=6.0 Hz), 8.30 (1H, d, J=1.5 Hz), 7.99 (1H, dd, J=8.0Hz, 1.5 Hz), 7.75-7.70 (1H, m), 7.62-7.50 (5H, m), 7.36 (1H, d, J=8.0Hz), 7.27-7.22 (1H, m), 3.08 (2H, brt, J=6.0 Hz), 2.32 (3H, s), 2.03(3H, s), 1.96-1.74 (1H, m), 0.87 (6H, d, J=7.0 Hz).

EXAMPLE 19(64)

2′-(4-amidinophenylcarbamoyl)-4-((cyclopropylmethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.51 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.52(1H, s), 9.16 (2H, s), 8.77 (2H, s), 8.76 (1H, br.t, J=6.2 Hz), 8.32(1H, d, J=2.0 Hz), 7.98 (1H, dd, J=2.0,8.0 Hz), 7.73 (4H, s), 7.70 (1H,dd, J=2.0,8.0 Hz), 7.58 (1H, dt, J=2.0,8.0 Hz), 7.53 (1H, dt, J=2.0,8.0Hz), 7.33 (1H, d, J=8.0 Hz), 7.28 (1H, dd, J=2.0,8.0 Hz), 3:15 (2H, t,J=6.2 Hz, 2.35 (3H, s), 1.04 (1H, m), 0.40-0.48 (2H, m), 0.19-0.27 (2H,m).

EXAMPLE 19(65)

2′-(4-amidinophenylcarbamoyl)-4-((1-methylcarbamoyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC: Rf 0.15 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ9.07 (4H, br s), 8.37 (1H, d, J=8.0 Hz), 8.06 (1H, s), 7.98 (1H, d,J=4.6 Hz), 7.74-7.57 (6H, m), 7.48-7.44 (2H, m), 7.07-7.02 (1H, m), 6.98(1H, d, J=8.0 Hz), 4.15 (1H, t, J=8.2 Hz), 2.56 (3H, d, J=4.4 Hz), 2.32(3H, s) 2.15-1.98 (1H, m), 0.88-0.83 (6H, m).

EXAMPLE 19(66)

2′-(4-amidinophenylcarbamoyl)-4-((cyclopentylmethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.31 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.52 (1H, s), 9.16 (2H, s), 8.83 (2H, s), 8.66 (1H, br.d, J=6.2 Hz),8.30 (1H, d, J=1.8 Hz), 7.97 (1H, dd, J=1.8,8.0 Hz), 7.73 (4H, s), 7.71(1H, dd, J=1.8,8.0 Hz), 7.53-7.58 (2H, m), 7.32 (1H, d, J=8.0 Hz), 7.27(1H, dd, J=1.8,8.0 Hz), 3.19 (2H, t, J=6.2 Hz), 2.35 (3H, s), 2.16 (1H,m), 1.53-1.69 (6H, m), 1.22-1.24 (2H, m).

EXAMPLE 19(67)

2′-(4-amidinophenylcarbamoyl)-4-((cyclobutylmethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.27 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.53 (1H, s), 9.17 (2H, s), 8.87 (2H, s), 8.64 (1H, br.d, J=6.6 Hz),8.30 (1H, d, J=1.8 Hz), 7.96 (1H, dd, J=1.8,8.0 Hz), 7.74 (4H, s), 7.71(1H, dd, J=1.8,8.0 Hz), 7.53-7.58 (2H, m), 7.32 (1H, d, J=8.0 Hz), 7.27(1H, dd, J=1.8,8.0 Hz), 3.30 (2H, t, J=6.6 Hz), 2.58 (1H, m), 2.35 (3H,s), 1.66-2.00 (6H, m).

EXAMPLE 19(68)

2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)sulfamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.38 (Chloroform:Methanol:Water=8:2:0.1); NMR (d₆-DMSO): δ 10.6(1H, br s), 9.14 (2H, br s), 8.79 (2H, br s), 8.20 (1H, d, J=1.8 Hz),7.89 (1H, dd, J=1.8, 8.2 Hz), 7.80-7.62 (5H, m), 7.62-7.50 (2H, m), 7.45(1H, d, J=8.2 Hz), 7.33-7.29 (1H, m), 2.60-2.40 (2H, m), 2.30 (3H, s),1.70-1.50 (1H, m), 0.78 (6H, d, J=6.6 Hz).

EXAMPLE 19(69)

2′-(4-amidinophenylcarbamoyl)-5-chloro-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.25 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.2-12.4 (1H, broad), 10.50 (1H, s), 9.14 (2H, s), 8.87 (2H, s),7.90-7.40 (9H, m), 7.40-7.26 (2H, m), 2.35 (3H, s).

EXAMPLE 19(70)

3-(2-(4-amidinophenylcarbamoyl)phenyl)-2-naphthalenecarboxylic acidmethanesulfonate

TLC: Rf 0.52 (Ethyl acetate:Acetic acid:Water=3:1:0.5); NMR (d₆-DMSO): δ10.44 (1H, s), 9.09 (2H, br.s), 8.78 (2H, br.s), 8.46 (1H, s), 8.07 (1H,d, J=8.0 Hz), 7.92 (1H, d, J=8.0 Hz), 7.76 (1H, s), 7.8-7.5 (9H, m),7.36 (1H, d, J=8.0 Hz), 4.31 (1H, br), 2.35 (3H, s).

EXAMPLE 19(71)

2′-(3-amidinophenylcarbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC: Rf 0.50 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.37(1H, s), 9.27 (2H, s), 8.93 (2H, s), 8.05 (1H, s), 7.83 (1H, d, J=7.8Hz), 7.63-7.67 (2H, m), 7.48-7.54 (4H, m), 7.37-7.46 (2H, m), 7.22-7.25(2H, m), 2.35 (3H, s).

EXAMPLE 19(72)

2-(2-(4-amidinophenylcarbamoyl)phenyl)cinnamic acid methanesulfonate

TLC: Rf 0.17 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.6-12.0 (1H, broad), 10.68 (1H, s), 9.14 (2H, brs), 8.86 (2H, brs),7.85-7.59 (8H, m), 7.45-7.24 (5H, m), 6.38 (1H, d, J=16 Hz), 2.34 (3H,s).

EXAMPLE 19(73)

2′-(4-amidinophenylcarbamoyl)biphenyl-2-yloxyacetic acidmethanesulfonate

TLC: Rf 0.10 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.3-12.6 (1H, broad), 10.42 (1H, s), 9.15 (2H, brs), 8.87 (2H, brs),7.75 (4H, s), 7.65-7.44 (4H, m), 7.28-7.21 (2H, m), 6.98 (1H, t, J=8.0Hz), 6.84 (1H, d, J=8.0 Hz), 4.45 (2H, s), 2.35 (3H, s).

EXAMPLE 19(74)

3-(2-(4-amidinophenylcarbamoyl)-4-methylphenyl)-2-naphthaleneoarboxylicacid methanesulfonate

TLC: Rf 0.17 (Chloroform:Methanol:Acetic acid=4:1:0.1); NMR (d₆DMSO): δ13.0-12.6 (1H, br), 10.44 (1H, s), 9.09 (2H, s), 8.74 (2H, s), 8.45 (1H,s), 8.06 (1H, d, J=6.4 Hz), 7.92 (1H, d, J=8.8 Hz), 7.8-7.5 (5H, m),7.73 (1H, s), 7.66 (2H, s), 7.40 (1H, d, J=8.4 Hz), 7.25 (1H, d, J=8.0Hz), 2.46 (3H, s), 2.33 (3H, s).

EXAMPLE 19(75)

1-(2-(4-amidinophenylcarbamoyl)phenyl)-2-naphthalenecarboxylic acidmethanesulfonate

TLC: Rf 0.14 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.3-12.7 (1H, broad), 10.50 (1H, s), 9.09 (2H, brs), 8.81 (2H, brs),7.99-7.95 (2H, m), 7.91-7.81 (2H, m), 7.67-7.51 (7H, m), 7.42 (1H, t,J=8.0 Hz), 7.26-7.20 (2H, m), 2.33 (3H, s).

EXAMPLE 19(76)

2-(3-(4-amidinophenylcarbamoyl)-6-methoxynaphthalen-2-yl)benzoic acidmethanesulfonate

TLC: Rf 0.38 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ12.62 (1H, br.s), 10.58 (1H, br.s), 9.14 (2H, br.s), 8.78 (2H, br.s),8.15 (1H, s), 7.91 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=7.8 Hz), 7.74 (4H,like s), 7.71 (1H, s), 7.6-7.2 (5H, m), 3.91 (3H, s), 2.31 (3H, s).

EXAMPLE 19(77)

3-(2-(4-amidinophenylcarbamoyl)-4-methoxyphenyl)-2-naphthalenecarboxylicacid methanesulfonate

TLC: Rf 0.20 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.8 (1H, brs), 10.46 (1H, s), 9.10 (2H, brs), 8.82 (2H, brs), 8.43 (1H,s), 8.08-8.03 (1H, m), 7.94-7.88 (1H, m), 7.74-7.52 (7H, m), 7.28 (1H,d, J=8.0 Hz), 7.24 (1H, d, J=3.0 Hz), 7.15 (1H, dd, J=8.0 Hz, 3.0 Hz),3.89 (3H, s), 2.33 (3H, s).

EXAMPLE 19(78)

3-(2-(4-amidinophenylcarbamoyl)-4-propoxyphenyl)-2-naphthalenecarboxylicacid methanesulfonate

TLC: Rf 0.18 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.8 (1H, brs), 10.45 (1H, s), 9.10 (2H, brs), 8.83 (2H, brs), 8.43 (1H,s), 8.08-8.02 (1H, m), 7.94-7.89 (1H, m), 7.73 (1H, s), 7.67 (4H, s),7.62-7.56 (2H, m), 7.26 (1H, d, J=8.0 Hz), 7.23 (1H, d, J=2.5 Hz), 7.14(1H, dd, J=8.0 Hz, 2.5 Hz), 4.06 (2H, t, J=7.0 Hz), 2.34 (3H, s), 1.79(2H, sextet, J=7.0 Hz), 1.03 (3H, t, J=7.0 Hz).

EXAMPLE 19(79)

2-(3-(4-amidinophenylcarbamoyl)-7-methoxynaphthalen-2-yl)benzoic acidmethanesulfonate

TLC: Rf 0.23 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ12.6-11.9 (1H, br), 10.57 (1H, s), 9.15 (2H, br.s), 8.82 (2H, br.s),8.20 (1H, s), 8.00 (1H, d, J=8.8 Hz), 7.85 (1H, d, J=7.4 Hz), 7.9-7.6(5H, m), 7.55 (1H, m), 7.5-7.3 (2H, m), 7.4-7.1 (2H, m), 3.89 (3H, m),2.33 (3H, s).

EXAMPLE 19(80)

2-(3-(4-amidinophenylcarbamoyl)-5-methoxynaphthalen-2-yl)benzoic acidmethanesulfonate

TLC: Rf 0.41 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ12.70 (1H, br), 10.66 (1H, s), 9.16 (2H, br.s), 8.87 (2H, br.s), 8.44(1H, s), 7.86 (1H, dd, J=1.4, 7.8 Hz), 7.75 (4H, s), 7.6-7.5 (4H, m),7.43 (1H, dt, J=1.4, 7.8 Hz), 7.32 (1H, dd, J=1.4, 7.8 Hz), 7.09 (1H,m), 4.04 (3H, s), 2.34 (3H, s).

EXAMPLE 19(81)

2′-(4-amidinophenylcarbamoyl)-4-nitro-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.13 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.5-12.8 (1H, broad), 10.68 (1H, s), 9.15 (2H, brs), 8.87 (2H, brs),8.56 (1H, d, J=2.5 Hz), 8.37 (1H, dd, J=8.0 Hz, 2.5 Hz), 7.81-7.70 (5H,m), 7.66-7.54 (2H, m), 7.53 (1H, d, J=8.0 Hz), 7.34-7.29 (1H, m), 2.35(3H, s).

EXAMPLE 19(82)

2′-(4-amidinophenylcarbamoyl)-4-methylsulfonylamino-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.33 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.40(1H, s), 9.98 (1H, s), 9.14 (2H, brs), 8.89 (2H, brs), 7.74 (2H, d,J=9.0 Hz), 7.67 (2H, d, J=9.0 Hz), 7.66-7.60 (2H, m), 7.58-7.43 (2H, m),7.32 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.23 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.20(1H, d, J=8.0 Hz), 2.96 (3H, s), 2.34 (3H, s).

EXAMPLE 19(83)

2′-(4-amidinophenylcarbamoyl)-4-chloro-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.49 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.52(1H, s), 9.15 (2H, s), 8.86 (2H, s), 7.81 (1H, d, J=2.0 Hz), 7.74 (4H,s), 7.69 (1H, dd, J=2.0,7.6 Hz), 7.53-7.62 (3H, m), 7.27 (1H, dd,J=2.0,7.6 Hz), 7.26 (1H, d, J=7.6 Hz), 2.33 (3H, s).

EXAMPLE 19(84)

2′-(4-amidinophenylcarbamoyl)biphenyl-2-ylacetic acid methanesulfonate

TLC: Rf 0.33 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.7-12.4 (1H, broad), 10.26 (1H, s), 9.14 (2H, brs), 8.91 (2H, brs),7.72-7.65 (3H, m), 7.60-7.48 (4H, m), 7.39-7.32 (2H, m), 7.29-7.08 (3H,m), 3.77 (1H, d, J=17 Hz), 3.55 (1H, d, J=17 Hz), 2.33 (3H, s).

EXAMPLE 19(85)

2′-(4-amidinophenylcarbamoyl)-5-nitro-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.24 (Chloroform:Methanol:Water=8:2:0.1); NMR (d₆-DMSO): δ 10.6(1H, s), 9.15 (2H, br s), 8.84 (2H, br s), 8.26 (1H, dd, J=2.6, 8.4 Hz),8.07-8.02 (2H, m), 7.85-7.58 (7H, m), 7.38 (1H, dd, J=2.2, 7.8 Hz), 2.39(3H, s).

EXAMPLE 19(86)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-methylaminomethyl-2-biphenylcarboxylicacid ditrifluoroacetate

TLC: Rf 0.57 (Chloroform:Methanol:Water=7:3:0.3); NMR (CD₃OD): δ 8.02(1H, d, J=1.6 Hz), 7.64-7.70 (6H, m), 7.54 (1H, dt, J=1.6,7.6 Hz), 7.50(1H, dt, J=1.6,7.6 Hz), 7.42 (1H, d, J=8.0 Hz), 7.23-7.28 (4H, m),7.10-7.15 (2H, m), 5.11 (2H, s), 4.23 (2H, s), 2.70 (3H, s).

EXAMPLE 19(87)

2′-(4-amidinophenylcarbamoyl)-4-ethoxycarbonylmethoxy-2-biphenylcarboxylic acid methanesulfonate

TLC: Rf 0.31 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ13.4-12.4 (1H, br), 10.67 (1H, br.s), 9.21 (2H, br.s), 9.05 (2H, br.s),7.8-7.5 (5H, m), 7.6-7.4 (2H, m), 7.3-7.0 (4H, m), 4.82 (2H, s), 4.14(2H, q, J=7.4 Hz), 2.34 (3H, s), 1.17 (3H, t, J=7.4 Hz).

EXAMPLE 19(88)

2′-(4-amidinophenylcarbamoyl)-4-((1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC: Rf 0.51 (Chloroform:Methanol:Water=7:3:0.3); NMR (CD₃OD): δ 9.04(2H, br.s), 8.61 (2H, br.s), 8.34 (1H, d, J=1.6 Hz), 7.96 (1H, dd,J=1.6,7.8 Hz), 7.64-7.74 (5H, m), 7.53-7.59 (2H, m), 7.38 (1H, d, J=7.8Hz), 7.26 (1H, dd, J=1.6,7.8 Hz), 4.47 (1H, d, J=6.6 Hz), 3.75 (3H, s),2.71 (3H, s), 2.26 (1H, septet, J=6.6 Hz), 1.02 (3H, d, J=6.6 Hz), 1.00(3H, d, J=6.6 Hz).

EXAMPLE 19(89)

2′-(4-amidinophenylcarbamoyl)-4-(2-(methoxymethoxy)ethoxy)-biphenylcarboxylicacid

TLC: Rf 0.54 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ13.0-12.0 (1H, br), 10.52 (1H, br.s), 9.3-9.0 (3H, br), 7.76 (2H, d,J=8.8 Hz), 7.67 (2H, d, J=8.8 Hz), 7.7-7.5 (1H, m), 7.6-7.4 (2H, m),7.30 (1H, d, J=2.6 Hz), 7.3-7.0 (3H, m), 4.60 (2H, s), 4.14 (2H, t,J=4.4 Hz), 3.76 (2H, t, J=4.4 Hz), 3.25 (3H, s).

EXAMPLE 19(90)

3-(2-(4-amidinophenylcarbamoyl)phenyl)-5-methoxymethoxy-2-naphthalenecarboxylicacid

TLC: Rf 0.50 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.80 (1H, br.s), 9.2-8.9 (3H, br), 8.39 (1H, s), 8.39 (1H, s), 7.95(1H, s), 7.8-7.6 (6H, m), 7.6-7.4 (3H, m), 7.34 (1H, m), 7.18 (1H, d,J=8.0 Hz), 5.35 (2H, s), 3.30 (3H, s).

EXAMPLE 19(91)

3-(2-(4-amidinophenylcarbamoyl)phenyl)-8-methoxymethoxy-2-naphthalenecarboxylicacid

TLC: Rf 0.62 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.69 (1H, br.s), 9.2-9.0 (3H, br), 8.69 (1H, s), 7.8-7.6 (6H, m),7.6-7.4 (4H, m), 7.33 (1H, dd, J=2.2, 7.4 Hz), 7.15 (1H, dd, J=3.0, 5.4Hz), 5.45 (2H, s), 3.46 (3H, s).

EXAMPLE 19(92)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)aminomethyl)-2-biphenylcarboxylicacid dimethanesulfonate

TLC: Rf 0.37 (Chloroform:Methanol:Water=8:2:0.1).

EXAMPLE 19(93)

2′-(4-amidinophenylcarbamoyl)-4-((2-methoxycarbonylethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.43 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ13.1-12.7 (1H, broad), 10.54 (1H, s), 9.15 (2H, brs), 8.88 (2H, b rs),8.75 (1H, brt, J=5.5Hz), 8.28 (1H, d, J=2.0 H z), 7.94 (1H, dd, J=8.0Hz, 2.0 Hz), 7.72 (4H, s), 7.69 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.62-7.47(2H, m), 7.32 (1H, d, J=8.0 Hz), 7.27 (1H, dd, J=7.5 Hz, 1.5 Hz), 3.59(3H, s), 3.49 (2H, q, J=7.0 Hz), 2.59 (2H, t, J=7.0 Hz), 2.34 (3H, s).

EXAMPLE 19(94)

2′-(4-amidinophenylcarbamoyl)-4-((3-ethoxycarbonylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.55 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ13.1-12.6 (1H, broad), 10.54 (1H, s), 9.16 (2H, brs), 8.91 (2H, brs),8.68 (1H, brt, J=5.5 Hz), 8.29 (1H, d, J=2.0 Hz), 7.96 (1H, dd, J=8.0Hz, 2.0 Hz), 7.73 (4H, s), 7.70 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.62-7.47(2H, m), 7.32 (1H, d, J=8.0 Hz), 7.27 (1H, dd, J=7.5 Hz, 1.5 Hz), 4.03(2H, q, J=7.0 Hz), 3.33-3.22 (2H, m), 2.34 (3H, s), 2.34 (2H, t, J=7.0Hz), 1.77 (2H, quint, J=7.0 Hz), 1.15 (3H, t, J=7.0 Hz).

EXAMPLE 19(95)

2′-(4-amidinophenylcarbamoyl)-4-((1-t-butoxycarbonylpiperidin-4-ylmethyl)carbamoyl)-2-biphenylcarboxylic acid

TLC: Rf 0.49 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.9 (1H, br s), 9.19 (2H, br s), 8.97 (2H, br s), 8.70 (1H, t, J=6.2Hz), 8.27 (1H, d, J=1.8 Hz), 7.94 (1H, dd, J=1.8, 8.0 Hz), 7.80-7.60(5H, m), 7.60-7.50 (2H, m), 7.30-7.23 (2H, m), 3.93 (2H, br d, J=12.0Hz), 3.16 (2H, br s), 2.80-2.50 (2H, m), 1.80-1.60 (3H, m), 1.39 (9H,s), 1.10-0.99 (2H, m).

EXAMPLE 19(96)

2′-(4-amidinophenylcarbamoyl)-4-((2-methylthioethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.58 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ13.0-12.0 (1H, br), 10.52 (1H, s), 9.14 (2H, br.s), 8.83 (2H, br.s),8.79 (1H, br.t), 8.29 (1H, s), 7.96 (1H, d, J=8.0 Hz), 7.72 (4H, likes), 7.8-7.6 (1H, m), 7.6-7.5 (2H, m), 7.33 (1H, d, J=8.0 Hz), 7.4-7.2(1H, m), 3.45 (2H, br.q), 2.64 (2H, t, J=6.8 Hz), 2.34 (3H, s), 2.08(3H, s).

EXAMPLE 19(97)

2′-(4-amidinophenylcarbamoyl)-4-((2-methylsulfinylethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.24 (Chloroform:Methanol:Water=10:0.2); NMR (d₆-DMSO): δ 10.52(1H, s), 9.14 (2H, s), 8.96 (1H, br.t, J=1.4 Hz), 8.88 (2H, s), 8.30(1H, s), 7.96 (1H, d, J=8.2 Hz), 7.72 (4H, like s), 7.8-7.6 (1H, m),7.6-7.5 (2H, m), 7.34 (1H, d, J=8.2 Hz), 7.28 (1H, d, J=8.2 Hz), 6.0-4.6(1H, br), 3.8-3.5 (2H, br), 3.06 (1H, dt, J=13.8, 6.4 Hz), 2.88 (1H, dt,J=13.8, 6..8 Hz), 2.58 (3H, s), 2.38 (3H, s).

EXAMPLE 19(98)

2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-methylbenzoic acidmethanesulfonate

TLC: Rf 0.27 (Chloroform:Methanol:Acetic acid=4:1:0.1); NMR (d₆-DMSO): δ12.6 (1H, brs), 10.7 (1H, s), 9.17 (2H, s), 8.83 (2H, s), 8.25 (1H, s),8.15-8.05 (1H, m), 8.05-7.95 (1H, m), 7.77 (5H, s), 7.7-7.6 (3H, m),7.37 (1H, dt, J=8.2, 1.0 Hz), 7.22 (1H, d, J=7.8 Hz), 2.37 (3H, s), 2.33(3H, s).

EXAMPLE 19(99)

2-(2-(4-amidinophenylcarbamoyl)naphthalen-1-yl)benzoic acidmethanesulfonate

TLC: Rf 0.20 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.5 (1H, broad), 10.40 (1H, s), 9.15 (2H, brs), 8.87 (2H, brs),8.07 (1H, d, J=8.0 Hz), 8.05 (1H, d, J=8.0 Hz), 7.96 (1H, dd, J=7.5 Hz,1.5 Hz), 7.73 (1H, d, J=8.0 Hz), 7.72 (2H, d, J=9.0 Hz), 7.62 (2H, d,J=9.z), 7.58-7.42 (4H, m), 7.27 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.21 (1H, d,J=8.0 Hz), 2.33 (3H, s).

EXAMPLE 19(100)

2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-methoxybenzoic acidmethanesulfonate

TLC: Rf 0.13 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.7 (1H, brs), 10.63 (1H, s), 9.17 (2H, brs), 8.91 (2H, brs), 8.24 (1H,s), 8.11-8.05 (1H, m), 8.01-7.95 (1H, m), 7.77 (4H, s), 7.76 (1H, s),7.65-7.59 (2H, m), 7.36 (1H, d, J=2.5 Hz), 7.26 (1H, d, J=8.5 Hz), 7.14(1H, dd, J=8.5 Hz, 2.5 Hz), 3.81 (3H, s), 2.35 (3H, s).

EXAMPLE 19(101)

2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-propoxybenzoic acidmethanesulfonate

TLC: Rf 0.20 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.7 (1H, brs), 10.63 (1H, s), 9.16 (2H, brs), 8.88 (2H, brs), 8.24 (1H,s), 8.10-8.05 (1H, m), 8.00-7.95 (1H, m), 7.77 (4H, s), 7.75 (1H, s),7.67-7.59 (2H, m), 7.34 (1H, d, J=2.5 Hz), 7.24 (1H, d, J=8.0 Hz), 7.12(1H, dd, J=8.0 Hz, 2.5 Hz), 3.98 (2H, t, J=7.0 Hz), 2.34 (3H, s), 1.74(2H, sextet, J=7.0 Hz), 0.98 (3H, t, J=7.0 Hz).

EXAMPLE 19(102)

2′-(4-amidinophenylcarbamoyl)-4′-amino-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.22 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.49(1H, s), 9.21 (2H, brs), 9.03 (2H, brs), 7.81 (1H, dd, J=8.0 Hz, 1.5Hz), 7.75 (2H, d, J=9.0 Hz), 7.64 (2H, d, J=9.0 Hz), 7.56-7.47 (2H, m),7.44-7.35 (2H, m), 7.31 (1H, d, J=8.0 Hz), 7.26 (1H, d, J=8.0 Hz), 2.40(3H, s).

EXAMPLE 19(103)

2′-(4-amidinophenylcarbamoyl)-4′-chloro-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.48 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.56(1H, s), 9.14 (2H, s), 8.80 (2H, s), 7.85 (1H, dd, J=1.8,7.6 Hz), 7.73(2H, d, J=9.2 Hz), 7.71 (1H, d, J=1.8 Hz), 7.68 (2H, d, J=9.2 Hz), 7.61(1H, dd, J=1.8,7.6 Hz), 7.54 (1H, dt, J=1.8,7.6 Hz), 7.42 (1H, dt,J=1.8,7.6 Hz), 7.29 (1H, d, J=7.6 Hz), 7.24 (1H, dd, J=1.8,7.6 Hz), 2.33(3H, s).

EXAMPLE 19(104)

2′-(4-amidinophenylcarbamoyl)-4′-(2-methoxycarbonylethyl)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.16 (Chloroform:Methanol=4:1); NMR (d₆-DMSO): δ 12.9-12.6 (1H,br), 10.4 (1H, s), 9.17 (2H, s), 9.0-8.8 (2H br), 7.79 (1H, d, J=7.8Hz), 7.70 (2H, d, J=6.8 Hz), 7.68 (1H, s), 7.67 (1H, t, J=7.8 Hz), 7.51(1H, d, J=7.8 Hz), 7.5-7.3 (1H, m), 7.40 (2H, d, J=6.8 Hz), 7.22 (1H, d,7.8 Hz), 7.16 (1H, d, J=7.8 Hz), 3.62 (3H, s), 2.99 (2H, t, J=7.6 Hz),2.75 (2H, t, J=7.6 Hz), 2.34 (3H, s).

EXAMPLE 19(105)

Benzyl 2′-(4-amidinophenylcarbamoyl)-3′-benzyloxy-2-biphenylcarboxylicacid trifluoroacetate

TLC: Rf 0.28 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.53 (1H, s), 9.36 (2H, brs), 9.17 (2H, brs), 7.84 (1H, d, J=8 Hz),7.74 (2H, d, J=9 Hz), 7.65 (2H, d, J=9 Hz), 7.60-7.10 (15H, m), 6.86(1H, d, J=8 Hz), 5.20 (2H, s), 5.09 (2H, brs).

EXAMPLE 19(106)

2-(2,3-dihydro-2,2-dimethyl-6-(4-amidinophenylcarbamoyl)benzofuran-5-yl)benzoicacid trifluoroacetate

TLC: Rf 0.35 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.59 (1H, brs), 9.19 (2H, s), 9.12 (2H, s), 7.72 (1H, d, J=7 Hz), 7.71(2H, d, J=9 Hz), 7.62 (2H, d, J=9 Hz), 7.42 (1H, t, J=7 Hz), 7.33 (1H,t, J=7 Hz), 7.16 (1H, d, J=7 Hz), 7.02 (1H, s), 6.94 (1H, s), 3.07 (2H,s), 1.47 (6H, s).

EXAMPLE 19(107)

2′-(4-amidinophenylcarbamoyl)-6′-methyl-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.21 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.5 (1H, broad), 10.36 (1H, s), 9.12 (2H, brs), 8.89 (2H, brs),7.86 (1H, d, J=8 Hz), 7.70 (2H, d, J=9 Hz), 7.60 (2H, d, J=9 Hz),7.57-7.35 (5H, m), 7.13 (1H, d, J=8 Hz), 2.37 (3H, s), 1.96 (3H, s).

EXAMPLE 19(108)

2′-(4-amidinophenylcarbamoyl)-5′-methyl-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.14 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.3-12.3 (1H, broad), 10.30 (1H, s), 9.14 (2H, brs), 8.91 (2H, brs),7.79 (1H, dd, J=8 Hz, 2 Hz), 7.73 (2H, d, J=9 Hz), 7.66 (2H, d, J=9 Hz),7.58 (1H, d, J=8 Hz), 7.51 (1H, td, J=8 Hz, 2 Hz), 7.40 (1H, td, J=8 Hz,2 Hz), 7.31 (1H, d, J=8 Hz), 7.21 (1H, d, J=8 Hz), 7.06 (1H, s), 2.38(6H, s).

EXAMPLE 19(109)

2′-(4-amidinophenylcarbamoyl)-4′-isopropyl-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.14 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.3-12.5 (1H, broad), 10.55 (1H, s), 9.15 (2H, brs), 9.05 (2H, brs),7.80-7.60 (5H, m), 7.52-7.32 (4H, m), 7.20 (1H, d, J=8 Hz), 7.16 (1H, d,J=8 Hz), 3.02 (1H, septet, J=7 Hz), 2.38 (3H, s), 1.30 (6H, d, J=7 Hz).

EXAMPLE 19(110)

2′-(4-amidinophenylcarbamoyl)-4′-t-butyl-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.14 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.6 (1H, broad), 10.35 (1H, s), 9.15 (2H, brs), 8.97 (2H, brs),7.82-7.34 (9H, m), 7.24 (1H, d, J=8 Hz), 7.19 (1H, d, J=8 Hz), 2.37 (3H,s), 1.38 (9H, s).

EXAMPLE 19(111)

2′-(4-amidinophenylcarbamoyl)-4′-ethyl-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.41 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 12.73(1H, brs), 10.42 (1H, s), 9.12 (2H, brs), 8.84 (2H, brs), 7.77 (1H, dd,J=7.6, 1.4 Hz), 7.74 (2H, d, J=9.0 Hz), 7.65 (2H, d, J=9.0 Hz),7.54-7.30 (4H, m), 7.21 (1H, dd, J=7.6, 1.2 Hz), 7.15 (1H, d, J=7.6 Hz),2.73 (2H, q, J=7.6 Hz), 2.33 (3H, s), 1.26 (3H, t, J=7.6 Hz).

EXAMPLE 19(112)

2′-(4-amidinophenylcarbamoyl)-4′-methoxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.61 (Chloroform:Methanol:Water=6:4:1); NMR (d₆-DMSO): δ13.2-12.5 (1H, broad), 10.51 (1H, s), 9.26 (2H, brs), 9.05 (2H, brs),7.88 (1H, dd, J=8 Hz, 1 Hz), 7.85 (2H, d, J=9 Hz), 7.77 (2H, d, J=9 Hz),7.59 (1H, td, J=8 Hz, 1 Hz), 7.49 (1H, td, J=8 Hz, 1 Hz), 7.32 (1H, dd,J=8 Hz, 1 Hz), 7.30 (1H, d, J=2 Hz), 7.23 (1H, d, J=8 Hz), 7.21 (1H, dd,J=8 Hz, 2 Hz), 3.97 (3H, s), 2.49 (3H, s).

EXAMPLE 19(113)

2-(5,6,7,8-tetrahydro-3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)benzoicacid methanesulfonate

TLC: Rf 0.37 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ13.0-12.6 (1H, broad), 10.32 (1H, s), 9.14 (2H, brs), 8.90 (2H, brs),7.78 (1H, dd, J=8 Hz, 2 Hz), 7.73 (2H, d, J=9 Hz), 7.66 (2H, d, J=9 Hz),7.56-7.36 (3H, m), 7.19 (1H, dd, J=8 Hz, 1 Hz), 6.92 (1H, s), 2.96-2.68(4H, m), 2.37 (3H, s), 1.92-1.68 (4H, m).

EXAMPLE 19(114)

2′-(4-amidinophenylcarbamoyl)-4′-cyano-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.32 (Chloroform:Methanol:Water 7:3:0.3); NMR (d₆-DMSO): δ13.0-12.5 (1H, broad), 10.66 (1H, s), 9.17 (2H, brs), 8.96 (2H, brs),8.16 (1H, d, J=1 Hz), 8.01 (1H, dd, J=8 Hz, 2 Hz), 7.90 (1H, dd, J=8 Hz,1 Hz), 7.76 (2H, d, J=9 Hz), 7.69 (2H, d, J=9 Hz), 7.62-7.40 (3H, m),7.26 (1H, dd, J=8 Hz, 1 Hz), 2.39 (3H, s).

EXAMPLE 19(115)

2-(6-(4-amidinophenylcarbamoyl)indan-5-yl)benzoic acid methanesulfonate

TLC: Rf 0.29 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ12.9-12.6 (1H, broad), 10.32 (1H, s), 9.14 (2H, brs), 8.86 (2H, brs),7.79 (1H, d, J=8 Hz), 7.73 (2H, d, J=9 Hz), 7.65 (2H, d, J=9 Hz),7.54-7.30 (3H, m), 7.19 (1H, d, J=7 Hz), 7.08 (1H, s), 3.06-2.82 (4H,m), 2.35 (3H, s), 2.20-2.00 (2H, m).

EXAMPLE 19(116)

2′-(4-amidinophenylcarbamoyl)-5′-methoxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.37 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.23(1H, s), 9.14 (2H, s), 8.79 (2H, s), 7.81 (1H, d, J=7.4 Hz), 7.72 (2H,d, J=8.8 Hz), 7.67 (1H, d, J=7.4 Hz), 7.66 (2H, d, J=8.8 Hz), 7.51 (1H,t, J=7.4 Hz), 7.40 (1H, t, J=7.4 Hz), 7.23 (1H, d, J=7.4 Hz), 7.05 (1H,dd, J=2.4,7.4 Hz), 6.76 (1H, d, J=2.4 Hz), 3.83 (3H, s), 2.33 (3H, s).

EXAMPLE 19(117)

2′-(4-amidinophenylcarbamoyl)-6′-methoxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.31 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆DMSO): δ 10.32(1H, s), 9.13 (2H, s), 8.82 (2H, s), 7.83 (1H, dd, J=1.4,7.6 Hz), 7.71(2H, d, J=9.0 Hz), 7.62 (2H, d, J=9.0 Hz), 7.46 (1H, t, J=8.0 Hz), 7.45(1H, dt, J=1.4,7.6 Hz), 7.35 (1H, dt, J=1.4,7.6 Hz), 7.13-7.23 (3H, m),3.67 (3H, s), 2.35 (3H, s).

EXAMPLE 19(118)

2′-(4-amidinophenylcarbamoyl)-5′-chloro-4-methyl-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.25 (Chloroform:Methanol:Acetic acid=4:1:0.1); NMR (d₆-DMSO): δ13.2-12.0 (1H, br), 10.5 (1H, s), 9.15 (2H, s), 8.84 (2H, s), 7.8-7.5(6H, m), 7.4-7.0 (1H, m), 7.35 (1H, d, J=8.0 Hz), 7.28 (1H, s), 7.15(1H, d, J=7.6 Hz), 2.37 (3H, s), 2.35 (3H, s).

EXAMPLE 19(119)

2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-methyl-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.34 (Chloroform:Methanol:Acetic acid=4:1:0.1); NMR (d₆-DMSO): δ12.67 (1H, s), 10.40 (1H, s), 9.14 (2H, s), 8.83 (2H, s), 7.74 (2H, d,J=9.4 Hz), 7.68 (2H, d, J=9.4 Hz), 7.60 (1H, s), 7.29(1H, dd, J=8.4, 2.0Hz), 7.18 (1H, d, J=2.4 Hz), 7.1-7.0 (3H, m), 3.87 (3H, s), 2.36 (3H,s), 2.33 (3H, s).

EXAMPLE 19(120)

2-(3-(4-amidinophenylcarbamoyl)-8-methoxynaphthalen-2-yl)benzoic acidmethanesulfonate

TLC: Rf 0.23 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ13.0-12.0 (1H, br), 10.65 (1H, s), 9.16 (2H, br.s), 8.84 (2H, br.s),8.22 (1H, s), 7.92 (1H, s), 7.85 (1H, dd, J=1.4, 7.4 Hz), 7.75 (4H, likes), 7.7-7.3 (4H, m), 7.32 (1H, dd, J=1.4, 7.4 Hz), 7.09 (1H, d, J=6.8Hz), 3.96 (3H, s), 2.33 (3H, s).

EXAMPLE 19(121)

2′-(4-amidinophenylcarbamoyl)-4′-dimethylcarbamoyl-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.25 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.52(1H, s), 9.16 (2H, s), 8.34 (2H, s), 7.85 (1H, dd, J=1.4,7.8 Hz), 7.74(2H, d, J=9.2 Hz), 7.69 (2H, d, J=9.2 Hz), 7.66 (1H, d, J=1.8 Hz), 7.57(1H, dd, J=1.8,7.8 Hz), 7.55 (1H, dt, J=1.4,7.8), 7.43 (1H, dt,J=1.4,7.8), 7.36 (1H, d, J=7.8), 7.28 (1H, dd, J=1.4,7.8), 3.03 (6H, s),2.34 (3H, s).

EXAMPLE 19(122)

2′-(4-amidinophenylcarbamoyl)-2,4′-biphenyldicarboxylic acidmethanesulfonate

TLC: Rf 0.14 (Chloroform:Methanol:Water=6:4:1); NMR (d₆-DMSO): δ 10.62(1H, s), 9.15 (2H, s), 8.86 (2H, s), 8.19 (1H, s), 8.08 (1H, d, J=7.8Hz), 7.87 (1H, d, J=7.2), 7.75 (2H, d, J=9.0 Hz), 7.70 (2H, d, J=9.0),7.56 (1H, t, J=7.2 Hz), 7.44 (1H, t, J=7.2 Hz), 7.41 (1H, d, J=7.8 Hz),7.26 (1H, d, J=7.2 Hz), 2.34 (3H, s).

EXAMPLE 19(123)

2′-(4-amidinophenylcarbamoyl)-4′-methylcarbamoyl-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.24 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.54(1H, s), 9.15 (2H, s), 8.87 (2H, s), 8.62 (1H, br.q, J=4.6 Hz), 8.13(1H, d, J=1.4 Hz), 7.99 (1H, dd, J=1.4,7.8 Hz), 7.86 (1H, dd, J=1.4,7.8Hz), 7.76 (2H, d, J=9.2 Hz), 7.71 (2H, d, J=9.2 Hz), 7.54(1H, dt,J=1.4,7.8 Hz), 7.43 (1H, dt, J=1.4,7.8 Hz), 7.35 (1H, d, J=7.8 Hz), 7.25(1H, dd, J=1.4,7.8 Hz), 2.85 (3H, br.d, J=4.6 Hz), 2.39 (3H, s).

EXAMPLE 19(124)

2′-(4-amidinophenylcarbamoyl)-4′-methylaminomethyl-2-biphenylcarboxylicacid dimethanesulfonate

TLC: Rf 0.30 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.41 (1H, s), 9.15 (2H, s), 8.89 (4H, s), 7.85 (1H, dd, J=1.6,7.8 Hz),7.83 (1H, d, J=1.6 Hz), 7.75 (2H, d, J=9.2 Hz), 7.67 (2H, d, J=9.2 Hz),7.66 (1H, dd, J=1.6,7.8 Hz), 7.54 (1H, dt, J=1.6,7.8 Hz), 7.43 (1H, dt,J=1.6,7.8 Hz), 7.34 (1H, d, J=7.8 Hz), 7.23 (1H, dd, J=1.6,7.8 Hz), 4.27(2H, br.s), 2.65 (3H, t, J=5.2 Hz), 2.37 (6H, s).

EXAMPLE 19(125)

2-(6-(4-amidinophenylcarbamoyl)-1,2-methylenedioxybenzen-5-yl)benzoicacid methanesulfonate

TLC: Rf 0.14 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.5 (1H, broad), 10.20 (1H, s), 9.12 (2H, brs), 8.84 (2H, brs),7.78 (1H, dd, J=8.0 Hz, 1.5 Hz), 7.71 (2H, d, J=9.0 Hz), 7.61 (2H, d,J=9.0 Hz), 7.48 (1H, td, J=7.5 Hz, 1.5 Hz), 7.37 (1H, td, J=7.5 Hz, 1.5Hz), 7.23 (1H, s), 7.21 (1H, dd, J=7.5 Hz, 1.5 Hz), 6.80 (1H, s), 6.15(2H, s), 2.34 (3H, s).

EXAMPLE 19(126)

2′-(4-amidinophenylcarbamoyl)-4′-(2-hydroxyethoxy)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.23 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ13.0-11.8 (1H, br), 10.39 (1H, s), 9.13 (2H, br.s), 8.80 (2H, br.s),7.8-7.6 (5H, m), 7.48 (1H, dt, J=1.0, 7.2 Hz), 7.37 (1H, dt, J=1.0, 7.2Hz), 7.3-7.0 (4H, m), 4.10 (2H, t, J=4.4 Hz), 3.76 (2H, t, J=4.4 Hz),3.8-3.3 (1H, br), 2.32 (3H, s).

EXAMPLE 19(127)

2′-(4-amidinophenylcarbamoyl)-4′-fluoro-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.47 (Chloroform:Methanol:Water 7:3:0.3); NMR (d₆-DMSO): δ 10.48(1H, s), 9.15 (2H, s), 8.87 (2H, s), 7.84 (1H, dd, J=1.6,7.8 Hz), 7.74(2H, d, J=8.8 Hz), 7.67 (2H, d, J=8.8 Hz), 7.24-7.56 (6H, m), 2.37 (3H,s).

EXAMPLE 19(128)

2-(3-(4-amidinophenylcarbamoyl)-8-hydroxynaphthalen-2-yl)benzoic acidmethanesulfonate

TLC: Rf 0.23 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.8-12.2 (1H, br), 10.62 (1H, s), 10.34 (1H, br.s), 9.17 (2H, br.s),8.87 (2H, br.s), 8.16 (1H, s), 7.90 (1H, s), 7.84 (1H, d, J=7.4 Hz),7.75 (4H, like s), 7.6-7.2 (5H, m), 6.99 (1H, d, J=6.4 Hz), 2.33 (3H,s).

EXAMPLE 19(129)

2′-(4-amidinophenylcarbamoyl)-4′-(2-methoxyethoxy)-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.40 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.2-11.6 (1H, br), 10.39 (1H, s), 9.13 (2H, s), 8.81 (2H, s), 7.8-7.6(5H, m),7.46 (1H, dt, J=1.6, 7.4 Hz), 7.37 (1H, dt, J=1.6,7.4 Hz),7.25-7.10 (4H, m), 4.21 (2H, t, J=4.6 Hz), 3.70 (2H, t, J=4.6 Hz), 3.33(3H, s), 2.33 (3H, s).

EXAMPLE 19(130)

2′-(4-amidinophenylcarbamoyl)-4′-trifluoromethoxy-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.29 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ10.5(1H, s), 9.15 (2H, br s), 8.83 (2H, br s), 7.86 (1H, dd, J=1.4, 7.0Hz), 7.76-7.47 (8H, m), 7.41 (1H, d, J=8.6 Hz), 7.29 (1H, dd, J=1.4, 7.6Hz), 2.36 (3H, s).

EXAMPLE 19(131)

2-(3-(4-amidinophenylcarbamoyl)-5-(2-methoxyethoxy)naphthalen-2-yl)benzoicacid methanesulfonate

TLC: Rf 0.55 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.0 (1H, br), 10.61 (1H, s), 9.16 (2H, brs), 8.84 (2H, brs), 8.41(1H, s), 7.85 (1H, d, J=6.3 Hz), 7.8-7.6 (4H, m), 7.6-7.4 (4H, m), 7.43(1H, t, J=7.4 Hz), 7.33 (1H, d, J=6.3 Hz), 7.10 (1H, t, J=4.4 Hz), 4.36(2H, t, J=4.4 Hz), 3.83 (2H, t, J=4.4 Hz), 3.37 (3H, s), 2.33 (3H, s).

EXAMPLE 19(132)

2-(3-(4-amidinophenylcarbamoyl)-5-hydroxynaphthalen-2-yl)benzoic acidmethanesulfonate

TLC: Rf 0.53 (Ethyl acetate:Acetic acid:Water=6:1:0.5); NMR (d₆-DMSO): δ13.0-12.0 (1H, br), 10.64 (1H, s), 10.48 (1H, br.s), 9.15 (2H, br.s),8.85 (2H, br.s), 8.43 (1H, s), 7.85 (1H, br.d, J=6.8 Hz), 7.51 (4H, likes), 7.67 (1H, s), 7.55 (1H, br.t, J=6.4 Hz), 7.5-7.3 (3H, m), 7.32 (1H,d, J=9.4 HZ), 6.97 (1H, dd, J=2.6, 6.0 Hz), 2.35 (3H, s).

EXAMPLE 19(133)

2′-(4-amidinophenylcarbamoyl)-4′-((methoxycarbonylmethyl)carbamoyl)-2-biphenylcarboxylicacid trifluoroacetate

TLC: Rf 0.34 (Chloroform:Methanol:Water=7:3:0.3); NMR (CD₃OD): δ 9.03(1H, m), 8.19 (1H, d, J=1.6 Hz), 8.02 (1H, dd, J=1.6,7.8 Hz), 7.92 (1H,dd, J=1.6,7.8 Hz), 7.70 (2H, d, J=9.0 Hz), 7.62 (2H, d, J=9.0 Hz), 7.53(1H, dt, J=1.6,7.8 Hz), 7.43 (1H, dt, J=1.6,7.8 Hz), 7.37 (1H, d, J=7.8Hz), 7.28 (1H, dd, J=1.6,7.8 Hz), 4.16-4.18 (2H, m), 3.77 (3H, s).

EXAMPLE 19(134)

2′-(4-amidinophenylcarbamoyl)-4′-((1-methoxycarbonyl-2-phenylethyl)carbamoyl)-2-biphenylcarboxylic acid trifluoroacetate

TLC: Rf 0.60 (Chloroform:Methanol:Water=7:3:0.3); NMR (CD₃OD): δ 8.84(1H, br.d, J=8.0 Hz), 8.06 (1H, s), 7.88-7.92 (2H, m), 7.70 (2H, d,J=9.2 Hz), 7.61 (2H, d, J=9.2 Hz), 7.39-7.56 (2H, m), 7.20-7.35 (7H, m),4.92 (1H, m), 3.75 (3H, s), 3.08-3.38 (2H, m).

EXAMPLE 19(135)

2′-(4-amidinophenylcarbamoyl)-4′-ethoxycarbonylmethoxy-2-biphenylcarboxylicacid methanesulfonate

TLC: Rf 0.30 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ12.71 (1H, br), 10.38 (1H, s), 9.13 (2H, br.s), 8.77 (2H, br.s), 7.9-7.6(5H, m), 7.49 (1H, m), 7.37 (1H, m), 7.3-7.0 (4H, m), 4.89 (2H, s), 4.20(2H, q, J=7.4 Hz), 2.31 (3H, s), 1.23 (3H, t, J=7.4 Hz).

EXAMPLE 19(136)

A mixture of 2-(6-(4-amidinophenylcarbamoyl)-1-benzyloxymethylbenzoimidazol-5-yl)benzoic acid trifluoroacetate and2-(5-(4-amidinophenylcarbamoyl)-1-benzyloxymethylbenzoimidazol-6-yl)benzoicacid trifluoroacetate

TLC: Rf 0.50 (Chloroform:Methanol:Water=7:3:0.3); NMR (CD₃OD): δ 8.52(0.5H, s), 8.47 (0.5H, s), 8.03 (0.5H, s), 8.01 (0.5H, s), 7.89 (0.5H,d, J=8.0 Hz), 7.86 (0.5H, d, J=8.0 Hz), 7.40-7.70 (7H, m), 7.24-7.28(6H, m), 5.86 (1H, s), 5.75 (1H, s), 4.62 (1H, s), 4.60 (1H, s).

EXAMPLE 19(137)

2′-(4-amidinophenylcarbamoyl)-4′-hydroxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.15 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.35(1H, s), 9.92 (1H, s), 9.22 (2H, s), 8.97 (2H, s), 7.75 (2H, d, J=8.8Hz), 7.74 (1H, d, J=7.6 Hz), 7.65 (2H, d, J=8.8 Hz), 7.47 (1H, t, J=7.6Hz), 7.35 (1H, t, J=7.6 Hz), 7.20 (1H, d, J=7.6 Hz), 7.04 (1H, d, J=8.6Hz), 7.03 (1H, d, J=2.4 Hz), 6.94 (1H, dd, J=2.4,8.6 Hz), 2:33 (3H, s).

EXAMPLE 19(138)

2′-(4-amidinophenylcarbamoyl)-5′-hydroxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.18 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.16(1H, s), 10.15 (1H, s), 9.20 (2H, s), 8.96 (2H, s), 7.78 (1H, dd,J=1.4,7.6 Hz), 7.74 (2H, d, J=9.0 Hz), 7.64 (2H, d, J=9.0 Hz), 7.56 (1H,d, J=8.4 Hz), 7.49 (1H, dt, J=1.4,7.6 Hz), 7.39 (1H, dt, J=1.4,7.6 Hz),7.18 (1H, dd, J=1.4,7.6 Hz), 6 87 (1H, dd, J=2.6,8.4 Hz), 6.59 (1H, d,J=2.6 Hz), 2.34 (3H, s).

EXAMPLE 19(139)

2′-(4-amidinophenylcarbamoyl)-4′-bromo-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.23 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.58(1H, s), 9.20 (2H, s), 8.93 (2H, s), 7.86 (1H, dd, J=1.6, 7.8 Hz), 7.84(1H, d, J=1.6 Hz), 7.74-7.78 (3H, m), 7.68 (2H, d, J=9.2 Hz), 7.53 (1H,dt, J=1.6,7.8 Hz), 7.42 (1H, dt, J=1.6,7.8 Hz), 7.25 (1H, dd, J=1.6,7.8Hz), 7.22 (1H, d, J=8.4 Hz), 2.35 (3H, s).

EXAMPLE 19(140)

2′-(4-amidinophenylcarbamoyl)-4-bromo-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.50 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.53(1H, s), 9.15 (2H, s), 8.79 (2H, s), 7.93-8.04 (3H, m), 7.74 (4H, s),7.52-7.58 (2H, m), 7.28 (1H, dd, J=1.8,7.6 Hz), 7.20 (1H, d, J=8.4 Hz),2.33 (3H, s).

EXAMPLE 19(141)

2′-(4-amidinophenylcarbamoyl)-3′-methoxy-2-biphenylcarboxylic acidmethanesulfonate

TLC: Rf 0.27 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.40(1H, br.s), 9.14 (2H, s), 8.86 (2H, s), 7.78 (1H, dd, J=1.8,7.6 Hz),7.70 (2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.27-7.47 (4H, m), 7.13(1H, d, J=8.0 Hz), 6.81 (1H, d, J=7.6 Hz), 3.84 (3H, s), 2.34 (3H, s).

EXAMPLE 19(142)

2′-(4-amidinophenylcarbamoyl)-4-((1-dimethylaminomethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid dimethanesulfonate

TLC: Rf 0.48 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ12.8-12.2(1H, br), 10.63 (1H, s), 9.21 (2H, s), 9.3-9.1 (1H, m), 9.00(2H, s), 8.59 (1H, d, J=9.2 Hz), 8.35 (1H, d, J=2.0 Hz), 8.06 (1H, dd,J=2.0, 8.0 Hz), 7.76 (4H, like s), 7.8-7.7 (1H, m), 7.7-7.5 (2H, m),7.35 (1H, d, J=8.0 Hz), 7.25 (1H, dd, J=2.0, 8.0 Hz), 4.20 (1H, m),3.4-3.2 (2H, m), 2.80 (3H, s), 2.78 (3H, s), 2.33 (6H, s), 1.84 (1H, m),0.92 (3H, d, J=7.4 Hz), 0.88 (3H, d, J=7.4 Hz).

EXAMPLE 19(143)

2′-(4-amidinophenylcarbamoyl)-4-((1-(pyrrolidin-1-ylmethyl)-2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid dimethanesulfonate

TLC: Rf 0.50 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ13.0-12.3 (1H, br), 10.61 (1H, br.s), 9.32 (1H, br), 9.17 (2H, br.s),8.94 (2H, br.s), 8.53 (1H, br.d, J=5.1 Hz), 8.36 (1H, d, J=1.2 Hz), 8.05(1H, dd, J-1.2, 7.8 Hz), 7.75 (4H, like s), 7.8-7.6 (1H, m), 7.6-7.5(2H, m), 7.35 (1H, d, J=7.8 Hz), 7.24 (1H, dd, J=1.2, 7.8 Hz), 4.18 (1H,m), 3.8-3.3 (4H, m), 3.2-3.0 (2H, m), 2.32 (6H, s), 2.1-1.8 (5H, m),0.93 (3H, d, J=6.6 Hz), 0.89 (3H, d, J=6.6 Hz).

EXAMPLE 19(144)

2′-(4-amidinophenylcarbamoyl)-4-((1-hydroxymethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC: Rf 0.48 (Ethyl acetate:Acetic acid:Water=3:1:0.5); NMR (d₆-DMSO): δ13.0-12.4 (1H, br), 10.52 (1H, br), 9.15 (2H, s), 8.89 (2H, s), 8.30(1H, d, J=1.5 Hz), 8.17 (1H, br), 7.98 (1H, dd, J=1.5, 8.0 Hz), 7.73(4H, like s), 7.8-7.6 (1H, m), 7.6-7.4 (2H, m), 7.31 (1H, d, J=8.0 Hz),7.26 (1H, dd, J=1.5, 8.0 Hz), 5.4-4.5 (1H, br), 3.81 (1H, m), 3.6-3.3(2H, m), 2.36 (3H, s), 1.90 (1H, like sextet, J=6.6 Hz), 0.90 (3H, d,J=6.6 Hz), 0.87 (3H, d, J=6.6 Hz).

EXAMPLE 19(145)

2-(6-(4-amidinophenylcarbamoyl)benzofuran-5-yl)benzoic acidmethanesulfonate

TLC: Rf 0.23 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.6 (1H, broad), 10.42 (1H, s), 9.14 (2H, brs), 8.86 (2H, brs),8.19 (1H, d, J=2.0 Hz), 7.94 (1H, d, J=1.0 Hz), 7.81 (1H, dd, J=8.0 Hz,1.5 Hz), 7.73 (2H, d, J=9.0 Hz), 7.67 (2H, d, J=9.0 Hz), 7.51 (1H, td,J=8.0 Hz, 1.5 Hz), 7.50 (1H, s), 7.40 (1H, td, J=8.0 Hz, 1.5 Hz), 7.27(1H, dd, J=8.0 Hz, 1.5 Hz), 7.05 (1H, dd, J=2.0 Hz, 1.0 Hz), 2.34 (3H,s).

EXAMPLE 19(146)

2-(5-(4-amidinophenylcarbamoyl)benzofuran-6-yl)benzoic acidmethanesulfonate

TLC:Rf 0.19 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.4 (1H, broad), 10.44 (1H, s), 9.14 (2H, brs), 8.86 (2H, brs),8.14 (1H, d, J=2.0 Hz), 7.98 (1H, s), 7.82 (1H, dd, J=8.0 Hz, 1.5 Hz),7.74 (2H, d, J=9.0 Hz), 7.67 (2H, d, J=9.0 Hz), 7.52 (1H, td, J=8.0 Hz,1.5 Hz), 7.48 (1H, d, J=1.0 Hz), 7.40 (1H, td, J=8.0 Hz, 1.5 Hz), 7.29(1H, dd, J=8.0 Hz, 1.5 Hz), 7.12 (1H, dd, J=2.0 Hz, 1.0 Hz), 2.34 (3H,s).

EXAMPLE 19(147)

2′-(4-amidinophenylaminomethyl)-4-((2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.32 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.97 (1H, br), 8.73 (2H, br.s), 8.56 (1H, br), 8.38 (2H, br.s), 8.36(1H, d, J=1.8 Hz), 8.04 (1H, dd, J=1.8, 7.8 Hz), 7.53 (2H, d, J=8.4 Hz),7.43 (1H, d, J=8.4 Hz), 7.4-7.2 (4H, m), 7.08 (1H, d, J=6.6 Hz), 6.55(2H, d, J=8.4 Hz), 4.07 (2H, br.s), 3.13 (2H, d, J=6.6 Hz), 2.34 (3H,s), 0.91 (9H, s).

EXAMPLE 19(148)

2′-(4-amidinophenylaminomethyl)-2-biphenylcarboxylic acidmethanesulfonate

TLC:Rf 0.51 (Chloroform: Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ12.9-12.6 (1H, broad), 8.74 (2H,s), 8.42 (2H, s), 7.89 (1H, d, J=8 Hz),7.67-7.42 (4H, m), 7.40-7.18 (5H, m), 7.07 (1H, t, J=4 Hz), 6.54 (2H, d,J=8 Hz), 4.06 (2H, d, J=4 Hz), 2.35 (3H, s).

EXAMPLE 19(149)

2-(3-(4-amidinophenylaminomethyl)naphthalen-2-yl)benzoic acidmethanesulfonate

TLC:Rf 0.21 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ13.2-12.5 (1H, br), 8.74 (2H, br.s), 8.34 (2H, br.s), 8.0-7.4 (10H, m),7.53 (2H, d, J=8.8 Hz), 7.5-7.2 (1H, br), 6.59 (2H, d, J=8.8 Hz), 4.18(2H, br.s), 2.32 (3H, s).

EXAMPLE 19(150)

2′-(4-amidinophenylaminomethyl)-4′-methoxy-2-biphenylcarboxylic acidmethanesulfonate

TLC:Rf 0.37 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.1-12.5 (1H, broad), 8.75 (2H, brs), 8.44 (2H, brs), 7.85 (1H, dd,J=7.5 Hz, 1.5 Hz), 7.61-7.43 (4H, m), 7.31 (1H, d, J=7.5 Hz), 7.25 (1H,brs), 7.00 (1H, d, J=9.0 Hz), 6.86-6.80 (2H, m), 6.54 (2H, d, J=9.0 Hz),4.02 (2H, brs), 3.70 (3H, s), 2.35 (3H, s).

EXAMPLE 19(151)

2-(3-(4-amidinophenylaminomethyl)naphthalen-2-yl)-5-((2-methylpropyl)carbamoyl) benzoic acid methanesulfonate

TLC:Rf 0.30 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 8.74(3H, br.s), 8.44 (1H, s), 8.31 (2H, s), 8.10 (1H, d, J=8.0 Hz),7.80-7.93 (2H, m), 7.75 (1H, s), 7.64 (1H, s), 7.47-7.56 (5H, m), 7.34(1H, br.s), 6.60 (2H, d, J=8.8 Hz), 4.22 (2H, br.s), 3.14 (2H, t, J=7.0Hz), 2.32 (3H, s), 1.89 (1H, m), 0.92 (6H, d, J=7.0 Hz).

EXAMPLE 19(152)

2′-(4-amidinophenylaminomethyl)-4′-methoxy-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.30 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 8.75(2H, s), 8.67 (1H, t, J=6.0 Hz), 8.34 (1H, d, J=2.0 Hz), 8.31 (2H, s),8.03 (1H, dd, J=2.0,8.0 Hz), 7.53 (2H, d, J=8.8 Hz), 7.41 (1H, d, J=8.0Hz), 7.24 (1H, br.s), 7.02 (1H, d, J=9.2 Hz), 6.86-6.88 (2H, m), 6.55(2H, d, J=8.8 Hz), 4.04 (2H, br.s), 3.72 (3H, s), 3.11 (2H, t, J=6.0Hz), 2.33 (3H, s), 1.87 (1H, m), 0.90 (6H, d, J=6.6 Hz).

EXAMPLE 19(153)

2′-(4-amidinophenylaminomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.42 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.4-9.6 (2H, broad), 8.60 (1H, brt, J=6.0 Hz), 8.51 (2H, brs), 8.30(1H, d, J=2.0 Hz), 7.87 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.47 (2H, d, J=9.0Hz), 7.48-7.35 (1H, broad), 7.32-7.15 (4H, m), 7.03-6.96 (1H, m), 6.66(2H, d, J=9.0 Hz), 4.25-3.95 (2H, m), 3.08 (2H, t, J=6.5 Hz), 2.34 (3H,s), 1.96-1.75 (1H, m), 0.88 (6H, d, J=7.0 Hz).

EXAMPLE 19(154)

Ethyl2′-(4-amidinophenylaminomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylatemethanesulfonate

TLC:Rf 0.58 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ8.70 (1H, brt, J=6.0 Hz), 8.80-8.40 (4H, broad), 8.34 (1H, s), 8.07 (1H,d, J=8.0 Hz), 7.54 (2H, d, J=8.5 Hz), 7.50 (1H, d, J=8.0 Hz), 7.40-7.17(4H, m), 7.06 (1H, d, J=7.5 Hz), 6.52 (2H, d, J=8.5 Hz), 4.17-3.90 (4H,m), 3.11 (2H, t, J=6.0 Hz), 2.32 (3H, s), 1.93-1.79 (1H, m), 0.91 (3H,t, J=0.89 (6H, d, J=7.0 Hz).

EXAMPLE 19(155)

Ethyl 2′-(4-(N²-hydroxyamidino)phenylaminomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate methanesulfonate

TLC:Rf 0.56 (Chloroform:Methanol:Water=9:1:0.1); NMR (d₆-DMSO): δ 12.26(1H, brs), 11.2-10.3 (1H, broad), 8.93 (1H, brs), 8.73 (1H, brt, J=6.0Hz), 8.56 (1H, brs), 8.34 (1H, d, J=2.0 Hz), 8.09 (1H, dd, 8.0 Hz, 2.0Hz), 7.50 (1H, d, J=8.0 Hz), 7.43 (2H, d, J=9.0 Hz), 7.36-7.23 (3H, m),7.06 (1H, d, J=7.0 Hz), 6.52 (2H, d, J=9.0 Hz), 4.16-3.90 (4H, m), 3.11(2H, t, J=6.0 Hz), 2.35 (3H, s), 1.97-1.76 (1H, m), 0.91 (3H, t, J=7.0Hz), 0.89 (6H, d, J=7.0 Hz).

EXAMPLE 19(156)

Ethyl 2′-(4-(N²-hydroxyamidino)phenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate methanesulfonate

TLC:Rf 0.24 (Chloroform:Methanol=10:1); NMR (d₆-DMSO): δ 12.60 (1H, br),11.05 (1H, br), 10.53 (1H, s), 9.3-8.8 (2H, br), 8.66 (1H, t, J=6.8 Hz),8.22 (1H, d, J=2.0 Hz), 8.02 (1H, dd, J=2.0, 7.8 Hz), 7.8-7.5 (7H, m),7.40 (1H, d, J=7.8 Hz), 7.31 (1H, br.d, J=7.8 Hz), 3.98 (2H, q, J=7.4Hz), 3.08 (2H, t, J=6.8 Hz), 2.33 (3H, s), 1.84 (1H, like septet, J=6.8Hz), 0.90 (3H, t, J=7.4 Hz), 0.88 (6H, d, J=6.8 Hz).

EXAMPLE 19(157)

Ethyl 2′-(4-(N²-hydroxyamidino)phenylcarbamoyl)-2-biphenylcarboxylatehydrochloride

TLC:Rf 0.37 (Chloroform:Methanol:Water=9:1:0.1); NMR (d₆-DMSO): δ 11.16(1H, brs), 10.42 (1H, s), 9.2-8.8 (3H, broad), 7.77 (1H, dd, J=8.0 Hz,1.5 Hz), 7.69 (2H, d, J=9.0 Hz), 7.64 (2H, d, J=9.0 Hz), 7.65-7.61 (1H,m), 7.59-7.48 (3H, m), 7.47 (1H, td, J=8.0 Hz, 1.5 Hz), 7.34-7.25 (2H,m), 3.96 (2H, q, J=7.0 Hz), 0.88 (3H, t, J=7.0 Hz).

EXAMPLE 19(158)

2′-(4-(N²-t-butoxycarbonyloxyamidino)phenylcarbamoyl)-2-biphenylcarboxylicacid

TLC:Rf 0.14 (Chloroform:Methanol:Water=9:1:0.1); NMR (d₆-DMSO): δ 10.09(1H, brs), 7.80 (1H, brd, J=7.0 Hz), 7.70-7.30 (9H, m), 7.21 (2H, d,J=8.5 Hz), 6.59 (2H, brs), 1.44 (9H, s).

EXAMPLE 19(159)

2′-(4-(N²-ethoxycarbonylamidino)phenylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.72 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.0 (1H, br), 11.13 (1H, br), 10.46 (1H, s), 10.42 (1H, br.s),7.81 (1H, dd, J=1.0, 7.4 Hz), 7.8-7.6 (5H, m), 7.6-7.3 (4H, m), 7.3-7.2(2H, m), 4.33 (2H, q, J=7.4 Hz), 4.0-3.0 (1H, br), 2.30 (3H, s), 1.31(3H, t, J=7.4 Hz).

EXAMPLE 19(160)

2-(4-(4-amidinophenylcarbamoyl)pyridin-3-yl)-5-((2-methylpropyl)carbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.50 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 11.03(1H, s), 9.23 (2H, brs), 9.00 (2H, brs), 8.88 (1H, d, J=5.5 Hz), 8.73(1H, brt, J=6.0 Hz), 8.71 (1H, s), 8.41 (1H, d, J=2.0 Hz), 8.05 (1H, dd,J=8.0 Hz, 2.0 Hz), 7.91 (1H, d, J=5.5 Hz), 7.78 (2H, d, J=9.5 Hz) 7.73(2H, d, J=9.5 Hz), 7.47 (1H, d, J=8.0 Hz), 3.09 (2H, brt, J=6.5 Hz),2.36 (3H, s), 1.97-1.75 (1H, m), 0.88 (6H, d, J=6.5 Hz).

EXAMPLE 19(161)

2-(2-(4-amidinophenylcarbamoyl)pyridin-3-yl)benzoic acidmethanesulfonate

TLC:Rf 0.34 (Ethyl acetate:Acetic acid:Water=3:1:0.5); NMR (d₆-DMSO): δ10.96 (1H,s), 9.21 (2H, br.s), 8.96 (2H, br.s), 8.71 (1H, m), 7.94 (2H,d, J=8.8 Hz), 8.0-7.8 (1H, m), 7.9-7.6 (2H, m), 7.77 (2H, d, J=8.8 Hz),7.60 (1H, t, J=7.4 Hz), 7.48 (1H, t, J=7.4 Hz), 7.24 (1H, d, J=7.4 Hz),5.6-4.2 (1H, br), 2.37 (3H, s).

EXAMPLE 19(162)

2′-(4-amidinophenylcarbamoyl)-4-propylcarbamoyl-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.09 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.13 (2H,brs), 8.79 (2H,brs), 8.64 (1H, t, J=5.4 Hz), 8.29(1H, d, J=1.8 Hz), 7.96 (1H, dd, J=1.8, 8.0 Hz), 7.80-7.60 (5H, m),7.58-7.51 (2H, m), 7.32 (1H, d, J=8.4 Hz), 7.30-7.20 (1H, m), 3.21 (2H,q, J=6.6 Hz), 2.33 (3H, s), 1.52 (2H, sextet, J=7.0 Hz), 0.88 (3H, t,J=7.0 Hz).

EXAMPLE 19(163)

2′-(4-amidinophenylcarbamoyl)-4-((3-hydroxy-2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.07 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ9.06 (4H, br s), 8.96 (1H, d, J=8.0 Hz), 8.44 (1H, t, J=5.4 Hz), 8.01(1H, s), 7.70-7.50 (6H, m), 7.50-7.40 (2H, m), 7.10-7.00 (1H, m), 6.97(1H, d, J=8.0 Hz), 4.59 (1H, t, J=5.8 Hz), 3.10-3.07 (4H, m), 2.31 (3H,s), 0.79 (6H, s).

EXAMPLE 19(164)

2′-(4-amidinophenylcarbamoyl)-4-((1,2,2-trimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.42 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.54 (1H, s), 9.16 (2H, s), 8.83 (2H, s), 8.29 (1H, d, J=1.8 Hz), 8.17(1H, br.d, J=9.4 Hz), 7.96 (1H, dd, J=1.8,8.0 Hz), 7.74 (4H, s), 7.71(1H, dd, J=1.8,8.0 Hz), 7.52-7.59 (2H, m), 7.31 (1H, d, J=8.0 Hz), 7.26(1H, m), 3.98 (1H, m), 2.36 (3H, s), 1.09 (3H, d, J=6.6 Hz), 0.91 (9H,s).

EXAMPLE 19(165)

2′-(4-amidinophenylcarbamoyl)-4-pentylcarbamoyl-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.39 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.52 (1H, s), 9.17 (2H, s), 8.89 (2H, s), 8.63 (1H, br.t, J=6.0 Hz),8.31 (1H, d, J=1.8 Hz), 7.97 (1H, dd, J=1.8,8.0 Hz), 7.74 (4H, s), 7.71(1H, dd, J=1.8,8.0 Hz), 7.52-7.59 (2H, m), 7.32 (1H, d, J=8.0 Hz), 7.28(1, m), 3.26 (2H, dt, J=6.0,6.6 Hz), 2.36 (3H, s), 1.50-1.56 (2H, m),1.26-1.33 (4H, m), 0.88 (3H, t, J=6.6 Hz).

EXAMPLE 19(166)

2′-(4-amidinophenylcarbamoyl)-4-hexylcarbamoyl-2-biphenylcarboxylic acidmethanesulfonate

TLC:Rf 0.26 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.14 (2H, br s), 8.84 (2H, br s), 8.62 (1H, t, J=5.4 Hz),8.28 (1H, d, J=2.1 Hz), 7.95 (1H, dd, J=2.1, 8.1 Hz), 7.75-7.67 (5H, m),7.60-7.48 (2H, m), 7.31 (1H, d, J=8.1 Hz), 7.28-7.25 (1H, m), 3.24 (2H,q, J=6.3 Hz), 2.34 (3H, s), 1.58-1.42 (2H, m), 1.38-1.20 (6H, m), 0.85(3H, t, J=6.3 Hz).

EXAMPLE 19(167)

2′-(4-amidinophenylcarbamoyl)-4-((1,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.23 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.15 (2H, br s), 8.85 (2H, br s), 8.33 (1H, d, J=9.0 Hz),9.0 Hz), 8.28 (1H, d, J=1.8 Hz), 7.96 (1H, dd, J=1.8, 7.8 Hz), 7.80-7.68(5H, m), 7.60-7.49 (2H, m), 7.30 (1H, d, J=7.8 Hz), 7.28-7.25 (1H, m),3.88-3.77 (1H, m), 2.34 (3H, s), 1.75 (1H, sextet, J=6.9 Hz), 1.09 (3H,d, J=6.9 Hz), 0.88 (6H, dd, J=2.7, 6.9 Hz).

EXAMPLE 19(168)

2′-(4-amidinophenylcarbamoyl)-4-(((1S)-1-hydroxymethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.48 (Ethyl acetate:Acetic acid:Water=3:1:0.5); NMR (d₆-DMSO): δ13.4-12.5 (1H, br), 10.54 (1H, s), 9.15 (2H, br.s), 8.91 (2H, br.s),8.31 (1H, d, J=1.4 Hz), 8.19 (1H, d, J=8.8 Hz), 7.99 (1H, dd, J=1.4, 8.0Hz), 7.73 (4H, like s), 7.8-7.5 (1H, m), 7.6-7.4 (2H, m), 7.32 (1H, d,J=8.0 Hz), 7.3-7.2 (1H, m), 5.2-3.6 (1H, br), 3.81 (1H, m), 3.6-3.4 (2H,m), 2.37 (3H, s), 1.90 (1H, like sextet, J=6.8 Hz), 0.90 (3H, d, J=6.8Hz), 0.86 (3H, d, J=6.8 Hz).

EXAMPLE 19(169)

2′-(4-amidinophenylcarbamoyl)-4-((3,3-dimethylbutyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.44 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.83 (1H, br.s), 10.53 (1H, s), 9.18 (2H, s), 8.92 (2H, s), 8.61 (1H,br.t, J=6.0 Hz), 8.29 (1H, d, J=1.8 Hz), 7.95 (1H, dd, J=1.8,8.0 Hz),7.74 (4H, s), 7.70 (1H, dd, J=1.8,8.0 Hz), 7.51-7.60 (2H, m), 7.32 (1H,d, J=8.0 Hz), 7.28 (1H, dd, J=1.8,8.0 Hz), 3.25-3.35 (2H, m), 2.36 (3H,s), 1.43-1.49 (2H, m), 0.93 (9H, s).

EXAMPLE 19(170)

2′-(4-amidinophenylcarbamoyl)-4-(((1R)-1-hydroxymethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.48 (Ethyl acetate:Acetic acid:Water=3:1:0.5); NMR (d₆-DMSO): δ12.4-11.6 (1H, br), 10.54 (1H, s), 9.15 (2H, br.s), 8.89 (2H, br.s),8.30 (1H, d, J=1.8 Hz), 8.19 (1H, d, J=9.0 Hz), 7.98 (1H, dd, J=1.8, 8.1Hz), 7.73 (4H, like s), 7.8-7.6 (1H, m), 7.65-7.45 (2H, m), 7.31 (1H, d,J=8.1 Hz), 7.26 (1H, dd, J=1.8, 8.1 Hz), 4.5-3.8 (1H, br), 3.81 (1H, m),3.6-3.4 (2H, m), 2.36 (3H, s), 1.90 (1H, like sextet, J=6.9 Hz), 0.89(3H, d, J=6.9 Hz), 0.86 (3H, d, J=6.9 Hz).

EXAMPLE 19(171)

2′-(4-amidinophenylcarbamoyl)-4-(((1S)-1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.36 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.14 (2H, br s), 8.85 (1H, d, J=7.6 Hz), 8.83 (2H, br s),8.33 (1H, d, J=1.8 Hz), 8.01 (1H, dd, J=1.8, 8.0 Hz), 7.80-7.68 (5H, m),7.59-7.52 (2H, m), 7.33 (1H, d, J=8.0 Hz), 7.30-7.25 (1H, m), 4.30 (1H,t, J=7.4 Hz), 3.65 (3H, s), 2.32 (3H, s), 2.32-2.10 (1H, m), 0.98-0.91(6H, m).

EXAMPLE 19(172)

2′-(4-amidinophenylcarbamoyl)-4-(((1R)-1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.36 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.15 (2H, br s), 8.85 (1H, d, J=7.4 Hz), 8.83 (2H, br s),8.33 (1H, d, J=1.8 Hz), 8.01 (1H, dd, J=1.8, 8.0 Hz), 7.80-7.68 (5H, m),7.59-7.50 (2H, m), 7.33 (1H, d, J=8.0 Hz), 7.30-7.25 (1H, m), 4.30 (1H,t, J=7.8 Hz), 3.65 (3H, s), 2.33 (3H, s), 2.33-2.10 (1H, m), 0.98-0.91(6H, m).

EXAMPLE 19(173)

2′-(4-amidinophenylcarbamoyl)-4-(3-methylbutoxy)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.26 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.4 (1H, s), 9.14 (2H, br s), 8.83 (2H, br s), 7.76-7.60 (5H, m),7.52-7.46 (2H, m), 7.30-7.05 (4H, m), 4.01 (2H, t, J=6.6 Hz), 2.33 (3H,s), 1.85-1.54 (3H, m), 0.91 (6H, d, J=6.6 Hz).

EXAMPLE 19(174)

2-(3-(4-amidinophenylcarbamoyl)pyridin-4-yl)-5-((2-methylpropyl)carbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.23 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 11.12(1H, s), 9.24 (2H, brs), 9.10 (1H, s), 9.03 (2H, brs), 8.90 (1H, d,J=5.5 Hz), 8.76 (1H, brt, J=5.5 Hz), 8.42 (1H, d, J=2.0 Hz) 8.08 (1H,dd, J=8.0 Hz, 2.0 Hz), 7.77 (4H, s), 7.70 (1H, d, J 5.5 Hz), 7.40 (1H,d, J=8.0 Hz), 3.09 (2H, t, J=6.0 Hz), 2.38 (3H, s), 1.95-1.75 (1H, m),0.88 (6H, d, J=6.5 Hz).

EXAMPLE 19(175)

2-(2-(4-amidinophenylcarbamoyl)benzothiophene-3-yl)benzoic acidmethanesulfonate

TLC:Rf 0.36 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.8 (1H, brs), 10.03 (1H, s), 9.17 (2H, brs), 8.89 (2H, brs), 8.13 (1H,d, J=8.0 Hz), 7.99 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.76 (2H, d, J=9.0 Hz),7.69-7.48 (5H, m), 7.45-7.36 (2H, m), 7.23 (1H, d, J=8.0 Hz), 2.34 (3H,s).

EXAMPLE 19(176)

Ethyl2′-(4-amidinophenoxymethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.56 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ9.15 (2H, brs), 8.92 (2H, brs), 8.71 (1H, brt, J=6.0 Hz), 8.31 (1H, d,J=2.0 Hz), 8.04 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.74 (2H, d, J=9.0 Hz),7.59-7.53 (1H, m), 7.44 (1H, d, J=8.0 Hz), 7.49-7.36 (2H, m), 7.17-7.12(1H, m), 7.01 (2H, d, J=9.0 Hz), 4.92 (1H, d, J=12 Hz), 4.85 (1H, d,J=12 Hz), 3.98 (2H, q, J=7.0 Hz), 3.08 (2H, t, J=6.0 Hz), 1.97-1.72 (1H,m), 0.88 (6H, d, J=7.0 Hz), 0.84 (3H, t, J=7.0 Hz).

EXAMPLE 19(177)

2-(3-(4-amidinophenylcarbamoyl)-5-methoxybenzofuran-2-yl)benzoic acidmethanesulfonate

TLC:Rf 0.14 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.2-12.8 (1H, broad), 10.48 (1H, brs), 9.17 (2H, brs), 8.89 (2H, brs),7.91 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.83 (2H, d, J=9.0 Hz), 7.78 (2H, d,J=9.0 Hz), 7.74 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.70 (1H, td, J=7.5 Hz, 1.5Hz), 7.62 (1H, td, J=7.5 Hz, 1.5 Hz), 7.60 (1H, d, J=9.0 Hz), 7.26 (1H,d, J=2.5 Hz), 7.03 (1H, dd, J=9.0 Hz, 2.5 Hz), 3.83 (3H, s), 2.34 (3H,s).

EXAMPLE 19(178)

Benzyl2′-(6-amidinopyridin-3-ylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.33 (Chloroform:Methanol:Acetic acid=8:2:0.1); NMR (CD₃OD): δ8.78 (1H, d, J=1.8 Hz), 8.33 (1H, d, J=1.8 Hz), 8.19 (1H, dd, J=2.6, 8.8Hz), 8.04 (1H, s), 7.99 (1H, dd, J=2.0, 8.0 Hz), 7.60-7.48 (2H, m), 7.44(1H, d, J=8.0 Hz), 7.33-7.29 (1H, m), 7.25-7.21 (3H, m), 7.14-7.09 (2H,m), 5.10 (2H, s), 3.18 (2H, d, J=7.0 Hz), 2.02-1.81 (1H, m), 0.95 (6H,d, J=6.6 Hz).

EXAMPLE 19(179)

2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((1,2,2-trimethylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.17 (Chloroform:Methanol:Water=10:2:1); NMR (d₆-DMSO): δ12.9-12.7 (1H, broad), 10.55 (1H, s), 9.17 (2H, brs), 8.91 (2H, brs),8.23 (1H, d, J=2.0 Hz), 8.16 (1H, d, J=9.5 Hz), 7.92 (1H, dd, J=8.0 Hz,2.0 Hz), 7.73 (4H, s), 7.28 (1H, d, J=8.0 Hz), 7.23 (1H, d, J=2.5 Hz),7.18 (1H, d, J=8.5 Hz), 7.13 (1H, dd, J=8.5 Hz, 2.5 Hz), 3.97 (1H, dq,J=9.5 Hz, 7.0 Hz), 3.87 (3H, s), 2.33 (3H, s), 1.08 (3H, t, J=7.0 Hz),0.89 (9H, s).

EXAMPLE 19(180)

2′-(4-amidinophenylcarbamoyl)-4-(((1S)-1-hydroxymethyl-2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.40 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.16 (2H, br s), 8.86 (2H, br s), 8.86 (1H, d, J=51.8 Hz),8.09 (1H, d, J=9.6 Hz), 7.98 (1H, dd, J=1.8, 8.0 Hz), 7.73-7.67 (5H, m),7.67-7.52 (2H, m), 7.31 (1H, d, J=8.0 Hz), 7.28-7.24 (1H, m), 4.40 (1H,br, s), 3.96-3.82 (1H, m), 3.70-3.62 (1H, m), 3.51-3.41 (1H, m), 2.33(3H, s), 0.88 (9H, s).

EXAMPLE 19(181)

Ethyl2′-(4-amidinophenylthiomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.67 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 9.25(2H, s), 8.97 (2H, s), 8.73 (1H, br.t, J=6.6 Hz), 8.37 (1H, d, J=1.8Hz), 8.08 (1H, dd, J=1.8, 8.0 Hz), 7.67 (2H, d, J=8.8 Hz), 7.53 (1H, m),7.45 (1H, d, J=8.0 Hz), 7.30-7.38 (4H, m), 7.10 (1H, m), 4.13 (1H, d,J=13.0 Hz), 4.04 (1H, d, J=13.0 Hz), 4.02 (2H, q, J=7.2 Hz), 3.12 (2H,t, J=6.6 Hz), 1.87 (1H, m), 0.91 (6H, d, J=6.6 Hz), 0.89 (3H, t, J=7.2Hz).

EXAMPLE 19(182)

Benzyl 2′-(6-amidinopyridin-3-ylcarbamoyl)-2-((1,2,2-trimethylpropyl)carbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.67 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.77 (1H, d, J=2.5 Hz), 8.25 (1H, d, J=2.0 Hz), 8.18 (1H, dd, J=8.5 Hz,2.5 Hz), 8.02 (1H, d, J=8.5 Hz), 7.93 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.42(1H, d, J=8.0 Hz), 7.27-7.17 (5H, m), 7.26-7.09 (2H, m), 7.08 (1H, dd,J=8.5 Hz, 2.5 Hz), 5.10 (2H, s), 4.05 (1H, q, J=7.0 Hz), 3.89 (3H, s),1.15 (3H, d, J=7.0 Hz), 0.95 (9H, s).

EXAMPLE 20-EXAMPLE 20(20)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 4, Example 2, Example 11 or Reference Example 8,using a compound prepared in Example 19(86)-Example 19(94), Example19(55), Example 19(95), Example 19(105), Example 19(133)-Example19(136), Example 19(158), Example 19(176), Example 19(178) and Example19(181)-Example 19(182).

EXAMPLE 20

2′-(4-amidinophenylcarbamoyl)-4-methylaminomethyl-2-biphenylcarboxylicacid dimethanesulfonate

TLC:Rf 0.29 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.55 (1H, s), 9.15 (2H, s), 8.92 (2H, s), 8.85 (2H, br.s), 8.01 (1H, d,J=1.8 Hz), 7.75 (4H, s), 7.70 (1H, dd, J=1.8,7.8 Hz), 7.62 (1H, dd,J=1.8,8.0 Hz), 7.52-7.58 (2H, m), 7.32 (1H, d, J=8.0 Hz), 7.25 (1H, dd,J=1.8,7.8 Hz), 4.20 (2H, t, J=5.6 Hz), 2.57 (3H, t, J=5.6 Hz), 2.37 (6H,s).

EXAMPLE 20(1)

2′-(4-amidinophenylcarbamoyl)-4-carboxymethoxy-2-biphenylcarboxylic acidmethanesulfonate

TLC:Rf 0.45 (Ethyl acetate:Acetic acid:Water=6:1:0.5); NMR (d₆-DMSO): δ13.4-12.5 (2H, br), 10.41 (1H, s), 9.20 (2H, br.s), 8.97 (2H, br.s),7.76 (2H, d, J=8.8 Hz), 7.69 (2H, d, J=8.8 Hz), 7.7-7.6 (1H, m), 7.6-7.4(2H, m), 7.28 (1H, d, J=2.8 Hz), 7.3-7.1 (2H, m), 7.06 (1H, dd, J=8.8,2.8 Hz), 4.72 (2H, s), 2.31 (3H, s).

EXAMPLE 20(2)

2′-(4-amidinophenylcarbamoyl)-4-((1-carboxy-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.12 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.57(1H, s), 9.24 (2H, s), 9.04 (?H, s), 8.68 (1H, d, J=7.8 Hz), 8.34 (1H,s), 8.02 (1H, d, J=7.8 Hz), 7.76 (5H, br.s), 7.52-7.60 (2H, m),7.26-7.36 (2H, m), 4.31 (1H, t, J=7.0 Hz), 2.37 (3H, s), 2.19 (1H, m),0.99 (3H, d, J=6.0 Hz), 0.97 (3H, d, J=6.0 Hz).

EXAMPLE 20(3)

2′-(4-amidinophenylcarbamoyl)-4-(2-hydroxyethoxy)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.22 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ13.1-12.0 (1H, br), 10.36 (1H, s), 9.13 (2H, br.s), 8.78 (2H, br.s),7.8-7.5 (5H, m), 7.6-7.4 (2H, m), 7.4-7.0 (4H, m), 4.00 (2H, t, J=4.8Hz), 3.69 (2H, t, J=4.8 Hz), 3.6-3.2 (1H, br), 2.31 (3H, s).

EXAMPLE 20(4)

3-(2-(4-amidinophenylcarbamoyl)phenyl)-5-hydroxy-2-naphthalenecarboxylicacid methanesulfonate

TLC:Rf 0.23 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.2 (1H, br), 10.45 (1H, s), 10.31 (1H, br.s), 9.09 (2H, br.s),8.75 (2H, br.s), 8.35 (1H, s), 7.91 (1H, s), 7.75-7.3 (10H, m), 6.94(1H, d, J=7.4 Hz), 2.31 (3H, s).

EXAMPLE 20(5)

3-(2-(4-amidinophenylcarbamoyl)phenyl)-8-hydroxy-2-naphthalenecarboxylicacid methanesulfonate

TLC:Rf 0.34 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.2-12.0 (1H, br), 10.6-10.4 (1H, br), 10.43 (1H, s), 9.12 (2H, brs),8.85 (2H, brs), 8.66 (1H, s), 7.8-7.5 (8H, m), 7.5-7.3 (3H, m), 6.92(1H, d, J=6.4 Hz), 2.32 (3H, s).

EXAMPLE 20(6)

2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)aminomethyl)-2-biphenylcarboxylicacid dimethanesulfonate

TLC:Rf 0.16 (Chloroform:Methanol:Water=8:2:0.1); NMR (d₆-DMSO): δ 10.6(1H, s), 9.16 (2H, br s), 8.94 (2H, br s), 8.75 (2H, br s), 8.05 (1H,s), 7.80-7.60 (6H, m), 7.60-7.50 (2H, m), 7.34-7.23 (2H, m), 4.22 (2H,br s), 2.79 (2H, br s), 2.39 (3H, s), 2.37 (3H, s), 2.06-1.93 (1H, m),0.94 (6H, d, J=6.6 Hz).

EXAMPLE 20(7)

2′-(4-amidinophenylcarbamoyl)-4-((2-carboxyethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.60 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ13.0-12.0 (2H, broad), 10.53 (1H, s), 9.18 (2H, brs), 8.92 (2H, brs),8.74 (1H, brt, J=5.5 Hz), 8.29 (1H, d, J=2.0 Hz), 7.95 (1H, dd, J=8.0Hz, 2.0 Hz), 7.28 (4H, s), 7.70 (1H, dd, J=7.5 Hz, 2.0 Hz), 7.62-7.47(2H, m), 7.32 (1H, d, J=8.0 Hz), 7.27 (1H, dd, J=7.5 Hz, 2.0 Hz), 3.45(2H, q, J=7.0 Hz), 2.51 (2H, t, J=7.0 Hz), 2.34 (3H, s).

EXAMPLE 20(8)

2′-(4-amidinophenylcarbamoyl)-4-((3-carboxypropyl)carbamoyl)-2-biphenylcarboxylicacid hydrochloride

TLC:Rf 0.65 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ12.8-12.1 (2H, broad), 10.57 (1H, s), 9.25 (2H, brs), 9.04 (2H, brs),8.71 (1H, brt, J=6.0 Hz), 8.30 (1H, d, J=2.0 Hz), 7.97 (1H, dd, J=7.5Hz, 2.0 Hz), 7.77 (2H, d, J=9.0 Hz), 7.71 (2H, d, J=9.0 Hz), 7.70 (1H,dd, J=7.5 Hz, 2.0 Hz), 7.62-7.47 (2H, m), 7.31 (1H, d, J=8.0 Hz), 7.26(1H, dd, J=7.5 Hz, 2.0 Hz), 3.27 (2H, q, J=6.0 Hz), 2.27 (2H, t, J=7.0Hz), 1.74 (2H, quint, J=7.0 Hz).

EXAMPLE 20(9)

2′-(4-amidinophenylcarbamoyl)-4-((5-aminopentyl)carbamoyl)-2-biphenylcarboxylicacid dimethanesulfonate

TLC:Rf 0.11 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.6 (1H, s), 9.15 (2H, br s), 8.90 (2H, br s), 8.66 (1H, t, J=5.6 Hz),8.31 (1H, d, J=1.8 Hz), 7.98 (1H, dd, J=1.8, 8.0 Hz), 7.81-7.35 (7H, m),7.35-7.26 (2H, m), 4.20 (3H, br s), 3.28 (2H, q, J=6.2 Hz), 2.79 (2H, q,J=7.4 Hz), 2.37 (3H, s), 2.36 (3H, s), 1.70-1.20 (6H, m).

EXAMPLE 20(10)

2′-(4-amidinophenylcarbamoyl)-4-((piperidin-4-ylmethyl)carbamoyl)-2-biphenylcarboxylicacid dimethanesulfonate

TLC:Rf 0.16 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.6 (1H, s), 9.17 (2H, br s), 8.95 (2H, br s), 8.78 (1H, t, J=6.0 Hz),8.58-8.55 (1H, m), 8.32 (1H, d, J=1.8 Hz), 8.25-8.21 (1H, m), 7.99 (1H,dd, J=1.8, 7.8 Hz), 7.78-7.70 (5H, m), 7.60-7.53 (2H, m), 7.35-7.27 (2H,m), 3.29-3.17 (4H, m), 2.89-2.79 (2H, m), 2.39 (6H, s), 1.84-1.80 (3H,m), 1.42-1.30 (2H, m).

EXAMPLE 20(11)

2′-(4-amidinophenylcarbamoyl)-3′-hydroxy-2-biphenylcarboxylic acidmethanesulfonate

TLC:Rf 0.27 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ13.0-12.0 (1H, broad), 10.34 (1H, s), 10.20-9.85 (1H, broad), 9.13 (2H,brs), 8.94 (2H, brs), 7.76 (1H, d, J=7 Hz), 7.72 (2H, d, J=9 Hz), 7.63(2H, d, J=9 Hz), 7.50-7.18 (4H, m), 6.95 (1H, d, J=8 Hz), 6.63 (1H, d,J=8 Hz), 2.41 (3H, s).

EXAMPLE 20(12)

2′-(4-amidinophenylcarbamoyl)-4′-((carboxymethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.56 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.60 (1H, s), 9.15 (2H, s), 9.03 (1H, br.t, J=5.4 Hz), 8.81 (2H, s),8.17 (1H, d, J=1.6 Hz), 8.03 (1H, dd, J=1.8,8.0 Hz), 7.87 (1H, dd,J=1.6,7.8 Hz), 7.75 (2H, d, J=9.2 Hz), 7.70 (2H, d, J=9.2 Hz), 7.55 (1H,dd, J=1.8,8.0 Hz), 7.44 (1H, dt, J=1.8,8.0 Hz), 7.39 (1H, d, J=7.8 Hz),7.27 (1H, dd, J=1.8,8.0 Hz), 3.99 (2H, br.d, J=5.4 Hz), 2.34 (3H, s).

EXAMPLE 20(13)

2′-(4-amidinophenylcarbamoyl)-4′-((1-carboxy-2-phenylethyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.76 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.57 (1H, s), 9.16 (2H, s), 8.92 (1H, br.d, J=5.4 Hz), 8.87 (2H, s),8.09 (1H, s), 7.97 (1H, d, J=7.8 Hz), 7.87 (1H, d, J=7.8 Hz), 7.75 (2H,d, J=9.2 Hz), 7.70 (2H, d, J=9.2 Hz), 7.55 (1H, t, J=7.8 Hz), 7.44 (1H,t, J=7.8 Hz), 7.19-7.38 (7H, m), 4.70 (1H, m), 3.04-3.29 (2H, m), 2.35(3H, s).

EXAMPLE 20(14)

2′-(4-amidinophenylcarbamoyl)-4′-carboxymethoxy-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.44 (Ethyl acetate:Acetic acid:Water=6:1:0.5); NMR (d₆-DMSO): δ10.37 (1H, s), 9.14 (2H, br.s), 8.84 (2H, br.s), 7.8-7.6 (5H, m), 7.49(1H, t, J=6.8 Hz), 7.37 (1H, t, J=6.8 Hz), 7.3-7.0 (4H, m), 4.79 (2H,s), 4.4-2.8 (2H, br), 2.35 (3H, s).

EXAMPLE 20(15)

2-(6-(4-amidinophenylcarbamoyl)benzoimidazol-5-yl)benzoic aciddimethanesulfonate

TLC:Rf 0.16 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.57(1H, s), 9.37 (1H, s), 9.17 (2H, s), 8.82 (2H, s), 8.10 (1H, s), 7.86(1H, d, J=7.8 Hz), 7.75 (2H, d, J=9.0 Hz), 7.68 (2H, d, J=9.0 Hz), 7.63(1H, s), 7.56 (1H, t, J=7.8 Hz), 7.44 (1H, t, J=7.8 Hz), 7.30 (1H, d,J=7.8 Hz), 2.35 (6H, s).

EXAMPLE 20(16)

2′-(4-(N²-hydroxyamidino)phenylcarbamoyl)-2-biphenylcarboxylic acidhydrochloride

TLC:Rf 0.31 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.47 (1H, s), 8.92 (2H, brs), 7.80 (1H, dd, J=1.0, 8.0 Hz), 7.70-7.30(9H, m), 7.28-7.18 (2H, m), 3.80-3.00 (2H, m).

EXAMPLE 20(17)

2′-(4-amidinophenoxymethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.43 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.7 (1H, broad), 9.08 (2H, brs), 8.84 (2H, brs), 8.67 (1H, brt,J=6.0 Hz), 8.33 (1H, d, J=2.0 Hz), 7.98 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.70(2H, d, J=9.0 Hz), 7.54-7.48 (1H, m), 7.39 (1H, d, J=8.0 Hz), 7.44-7.33(2H, m), 7.18-7.12 (1H, m), 7.04 (2H, d, J=9.0 Hz), 4.92 (2H, s), 3.08(2H, t, J=6.0 Hz), 2.31 (3H, s), 1.95-1.75 (1H, m), 0.88 (6H, d, J=7.0Hz).

EXAMPLE 20(18)

2′-(6-amidinopyridin-3-ylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.51 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.9(1H, s), 9.38 (2H, brs), 9.12 (2H, br s), 8.90 (1H, d, J=2.2 Hz), 8.66(1H, t, J=6.0 Hz), 8.29 (1H, d, J=1.8 Hz), 8.26-8.16 (2H, m), 7.98 (1H,dd, J=1.8, 8.0 Hz), 7.75 (1H, dd, J=1.8, 7.0 Hz), 7.68-7.52 (2H, m),7.35-7.28 (2H, m), 3.08 (1H, t, J=6.2 Hz), 2.34 (3H, s), 1.91-1.77 (1H,m), 0.88 (6H, d, J=6.6 Hz).

EXAMPLE 20(19)

2′-(4-amidinophenylthiomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.47 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 9.18(2H, s), 8.89 (2H, s), 8.70 (1H, br.t, J=6.3 Hz), 8.38 (1H, s), 8.03(1H, d, J=8.0 Hz), 7.64 (2H, d, J=8.8 Hz), 7.52 (1H, d, J=8.0 Hz), 7.40(1H, d, J=8.0 Hz), 7.30-7.38 (4H, m), 7.11 (1H, d, J=8.0 Hz), 4.17 (1H,d, J=13.6 Hz), 4.02 (1H, d, J=13.6 Hz), 3.11 (2H, t, J=6.3 Hz), 2.36(3H, s), 1.87 (1H, m), 0.90 (6H, d, J=6.3 Hz).

EXAMPLE 20(20)

2′-(6-amidinopyridin-3-ylcarbamoyl)-4′-methoxy-4-((1,2,2-trimethylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.19 (Chloroform:Methanol:Water=10:2:1); NMR (d₆-DMSO): δ13.0-12.0 (1H, broad), 10.88 (1H, s), 9.36 (2H, brs), 9.10 (2H, brs),8.91 (1H, d, J=2.5 Hz), 8.27 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.23 (1H, d,J=2.0 Hz), 8.17 (1H, d, J=9.0 Hz), 8.15 (1H, d, J=9.0 Hz), 7.94 (1H, dd,J=8.0 Hz, 2.0 Hz), 7.30 (1H, d, J=8.0 Hz), 7.29 (1H, d, J=2.0 Hz), 7.22(1H, d, J=8.5 Hz), 7.16 (1H, dd, J=8.5 Hz, 2.0 Hz), 3.98 (1H, dq, J=9.0Hz, 7.0 Hz), 3.88 (3H, s), 2.34 (3H, s), 1.07 (3H, d, J=7.0 Hz), 0.89(9H, s).

EXAMPLE 21

N-benzyloxy-2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxamide

The compound prepared in Example 19(1) (147 mg) and O-benzylhydroxyaminehydrochloride (178 mg) were dissolved into dimethylformamide (1 ml) andpyridine (1 ml). Dicyclohexylcarbodiimide (115 mg) was added to themixture. The mixture was stirred for 18 hours at room temperature. Thereaction mixture was filtered, and the solid was washed withdimethylformamide. The solution of washings and filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel (Chloroform:Methanol:Water=9:1:0.1→8:2 0.1) to give thepresent compound having the following physical data.

TLC:Rf 0.40 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.88 (1H, brs), 9.40-8.70 (3H, broad), 7.75-7.63 (3H, m), 7.60-7.46(4H, m), 7.46-7.32 (8H, m), 7.18-7.10 (2H, m), 4.73 (2H, s).

EXAMPLE 21(1)-EXAMPLE 21(10)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 21, using a compound prepared in Example 19(1),Example 19(41), Example 19(47)-Example 19(48), Example 6, Example19(100), Example 4, Example 19(112), Example 19(159) and Example 19(1),subject to using N-methyl-O-benzylhydroxyamine instead ofO-benzylhydroxyamine in Example 21(1), and using cyanamide instead ofO-benzylhydroxyamine in Example 21(10).

EXAMPLE 21(1)

N-benzyloxy-N-methyl-2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxamide

TLC:Rf 0.24 (Chloroform:Methanol:Acetic acid=20:2:1); NMR (d₆-DMSO): δ10.9-10.3 (1H, broad), 9.17 (3H, brs), 7.76-7.00 (17H, m), 4.84 (2H,brs), 3.17 (3H, brs).

EXAMPLE 21(2)

N-benzyloxy-2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxamide

TLC:Rf 0.31 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO) δ 10.92(1H, br.s), 9.08 (3H, br.s), 8.63 (1H, br.t, J=6.6 Hz), 8.01 (1H, d,J=1.8 Hz), 7.90 (1H, dd, J=1.8,8.0 Hz), 7.69-7.76 (3H, m), 7.55-7.62(4H, m), 7.37 (5H, s), 7.26 (1H, d, J=8.0 Hz), 7.16 (1H, m), 4.75 (2H,s), 3.07 (2H, t, J=6.6 Hz), 1.84 (1H, m), 0.88 (6H, d, J=6.6 Hz).

EXAMPLE 21(3)

N-benzyloxy-2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-((2-methylpropyl)carbamoyl)benzcarboxamide

TLC:Rf 0.28 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.24(1H, s), 8.06 (1H, m), 8.00 (1H, d, J=1.8 Hz), 7.94 (1H, m), 7.87 (1H,dd, J=1.8,8.0 Hz), 7.64-7.70 (7H, m), 7.35 (1H, d, J=8.0 Hz), 7.16-7.29(5H, m), 4.65 (2H, br.s), 3.18 (2H, d, J=7.0 Hz), 1.91 (1H, m), 0.95 (6,d, J=6.6 Hz).

EXAMPLE 21(4)

N-benzyloxy-2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxamide

TLC:Rf 0.28 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 7.93(1H, d, J=1.8 Hz), 7.82 (1H, dd, J=1.8,8.0 Hz), 7.68 (2H, d, J=9.2 Hz),7.61 (2H, d, J=9.2 Hz), 7.39 (5H, s), 7.26 (1H, d, J=8.0 Hz), 7.22 (1H,t, J=1.4 Hz), 7.10 (2H, d, J=1.4 Hz), 4.84 (2H, s), 3.90 (3H, s), 3.16(2H, d, J=7.4 Hz), 1.89 (1H, m), 0.94 (6H, d, J=6.6 Hz).

EXAMPLE 21(5)

N-benzyloxy-2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)benzcarboxamide

TLC:Rf 0.48 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ 11.21(1H, br), 9.11 (3H, br), 8.29 (1H, s), 8.11 (1H, m), 7.95 (1H, m),7.8-7.5 (7H, m), 7.6-7.3 (4H, m), 7.4-7.1 (6H, m), 4.63 (2H, s).

EXAMPLE 21(6)

N-benzyloxy-2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-methoxybenzcarboxamide

TLC:Rf 0.39 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ 11.87(1H, s), 11.04 (1H, s), 9.3-9.0 (3H, s), 8.27 (1H, s), 8.10 (1H, m),7.96 (1H, m), 7.78 (2H, d, J=9.4 Hz), 7.8-7.5 (4H, m), 7.5-7.1 (7H, m),7.1-6.9 (2H, m), 4.64 (2H, s), 3.77 (3H, s).

EXAMPLE 21(7)

N-benzyloxy-2′-(4-amidinophenylcarbamoyl)-4′-methyl-2-biphenylcarboxamide

TLC:Rf 0.52 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ 11.92(1H, br.s), 10.83 (1H, s), 9.4-8.8 (3H, br), 7.72 (3H, J=8.8 Hz), 7.52(2H, d, J=8.8 Hz), 7.6-7.2 (9H, m), 7.10 (1H, d, J=7.8 Hz), 7.03 (1H, d,J=7.8 Hz), 4.75 (2H, s), 2.40 (3H, s).

EXAMPLE 21(8)

N-benzyloxy-2′-(4-amidinophenylcarbamoyl)-4′-methoxy-2-biphenylcarboxamide methanesulfonate

TLC:Rf 0.62 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.68 (2H, d, J=9.0 Hz), 7.58 (2H, d, J=9.0 Hz), 7.45-7.28 (8H, m),7.22-7.11 (2H, m), 7.09-7.07 (2H, m), 4.82 (2H, s), 3.88 (3H, s).

EXAMPLE 21(9)

N-benzyloxy-2′-(4-(N²-ethoxycarbonylamidino)phenylcarbamoyl)-2-biphenylcarboxamide

TLC:Rf 0.58 (Toluene:Ethyl acetate=1:1); NMR (d₆-DMSO): δ 11.85 (1H,br.s), 10.70 (1H, s), 9.2-8.8 (2H, br), 7.85 (2H, d, J=8.8 Hz), 7.66(1H, m), 7.6-7.5 (2H, m), 7.5-7.3 (10H, m), 7.2-7.1 (2H, m), 4.71 (2H,s), 4.03 (2H, q, J=7.4 Hz), 1.20 (3H, t, J=7.4 Hz).

EXAMPLE 21(10)

N-cyano-2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxamidemethanesulfonate

TLC:Rf 0.34 (Ethyl acetate:Acetic acid:Water=6:1:0.5); NMR (d₆-DMSO): δ10.81 (1H, s), 9.17 (2H, br.s), 8.89 (2H, br.s), 7.74 (4H, like s),7.8-7.4 (6H, m), 7.29 (2H, t, J=8.0 Hz), 6.0-4.0 (1H, br), 2.35 (3H, s).

EXAMPLE 22-EXAMPLE 22(9)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 2, using the compound prepared in Example21-Example 21(9). Example 22

N-hydroxy-2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxamide

TLC:Rf0.14 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ11.8-11.2 (1H, broad), 11.21 (1H, s), 9.7-8.7 (4H, broad), 7.77-7.60(3H, m), 7.60-7.30 (7H, m), 7.20-7.04 (2H, m).

EXAMPLE 22(1)

N-hydroxy-N-methyl-2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxamidemethanesulfonate

TLC:Rf 0.29 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.41 (1H, brs), 10.03 (1H, brs), 9.10-8.55 (4H, broad), 7.70 (2H, d,J=7.0 Hz), 7.67-7.65 (1H, m), 7.53-7.47 (5H, m), 7.37-7.32 (2H, m),7.31-7.28 (1H, m), 7.15-7.13 (1H, m), 3.21 (3H, s), 2.37 (3H; s).

EXAMPLE 22(2)

N-hydroxy-2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxamidemethanesulfonate

TLC:Rf 0.42 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 11.53(1H, s), 11.18 (1H, s), 9.13 (2H, s), 8.85 (2H, s), 8.61 (1H, br.t,J=6.2 Hz), 8.02 (1H, d, J=1.8 Hz), 7.90 (1H, dd, J=1.8,8.0 Hz),7.68-7.73 (3H, m), 7.54-7.59 (4H, m), 7.23 (1H, d, J=8.0 Hz), 7.14 (1H,m), 3.0 (2H, t, J=6.2 Hz), 2.34 (3H, s), 1.82 (1H, m), 0.87 (6H, d,J=6.6 Hz).

EXAMPLE 22(3)

N-hydroxy-2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-((2-methylpropyl)carbamoyl)benzcarboxamidemethanesulfonate

TLC:Rf 0.19 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 11.49(1H, s), 11.31 (1H, s), 9.15 (2H, s), 8.81 (2H, s), 8.62 (1H, br.t,J=5.8 Hz), 8.33 (1H, s), 8.13 (1H, m), 8.06 (1H, d, J=1.8 Hz), 8.00 (1H,m), 7.93 (1H, dd, J=1.8,8.0 Hz), 7.61-7.75 (7H, m), 7.32 (1H, d, J=8.0Hz), 3.08 (2H, t, J=5.8 Hz), 2.34 (3H, s), 1.84 (1H, m), 0.89 (6H, d,J=6.6 Hz).

EXAMPLE 22(4)

N-hydroxy-2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxamide methanesulfonate

TLC:Rf 0.33 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 11.47(1H, s), 11.18 (1H, s), 9.14 (2H, s), 8.85 (2H, s), 8.60 (1H, br.t,J=5.8 Hz), 7.99 (1H, d, J=1.6 Hz), 7.87 (1H, dd, J=1.6,8.0 Hz), 7.70(2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.21 (1H, d, J=2.6 Hz), 7.20(1H, d, J=8.0 Hz), 7.14 (1H, dd, J=2.6,8.4 Hz), 7.06 (1H, d, J=8.4 Hz),3.86 (3H, s), 3.06 (2H, t, J=5.8 Hz), 2.34 (3H, s), 1.82 (1H, m), 0.87(6H, d, J=6.6 Hz).

EXAMPLE 22(5)

N-hydroxy-2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)benzcarboxamide methanesulfonate

TLC Rf 0.60 (Ethyl acetate:Acetic acid:Water=3:1:0.5); NMR (d₆-DMSO): δ11.49 (1H, s), 11.35 (1H, s), 9.5-9.2 (1H, br), 9.15 (2H, br.s), 8.82(2H, br.s), 8.30 (1H, s), 8.11 (1H, m), 7.98 (1H, m), 7.8-7.2 (10H, m),7.19 (1H, m), 2.30 (3H, s).

EXAMPLE 22(6)

N-hydroxy-2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-methoxybenzcarboxamide methanesulfonate

TLC:Rf 0.26 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ 11.46(1H, br.s), 11.33 (1H, s), 9.16 (2H, br.s), 8.87 (2H, br.s), 8.27 (1H,s), 8.10 (1H, t, J=4.4 Hz), 7.96 (1H, t, J=4.4 Hz), 7.8-7.5 (7H, m),7.2-6.9 (3H, m), 5.5-4.2 (1H, br), 3.77 (3H, s), 2.35 (3H, s).

EXAMPLE 22(7)

N-hydroxy-2′-(4-amidinophenylcarbamoyl)-4′-methyl-2-biphenylcarboxamidemethanesulfonate

TLC:Rf 0.29 (Chloroform:Methanol:Water=10:3:0.2); NMR (d₆-DMSO): δ 11.46(1H, s), 11.17 (1H, s), 9.41 (1H, br), 9.12 (2H, br.s), 8.81 (2H, br.s),7.68 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 7.46 (1H, s), 7.5-7.3(4H, m), 7.07 (1H, m), 7.01 (1H, d, J=7.8 Hz), 2.40 (3H, s), 2.31 (3H,s).

EXAMPLE 22(8)

N-hydroxy-2′-(4-amidinophenylcarbamoyl)-4′-methoxy-2-biphenylcarboxamide methanesulfonate

TLC:Rf 0.18 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ11.46 (1H, s), 11.21 (1H, s), 9.70-9.10 (1H, broad), 9.13 (2H, brs),8.89 (2H, brs), 7.69 (2H, d, J=9.0 Hz), 7.52 (2H, d, J=9.0 Hz),7.50-7.34 (3H, m), 7.20-7.02 (4H, m), 3.84 (3H, s), 2.35 (3H, s).

EXAMPLE 22(9)

N-hydroxy-2′-(4-(N²-ethoxycarbonylamidino)phenylcarbamoyl)-2-biphenylcarboxamide

TLC:Rf 0.59 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ11.44 (1H, br.s), 10.99 (1H, s), 9.42 (1H, s), 9.3-8.7 (2H, br), 7.83(2H, d, J=8.8 Hz), 7.65 (1H, m), 7.6-7.4 (3H, m), 7.5-7.3 (4H, m),7.2-7.0 (2H, m), 4.03 (2H, q, J=7.4 Hz), 1.19 (3H, t, J=7.4 Hz).

EXAMPLE 23-EXAMPLE 23(1)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 12, using compounds prepared in Example19(81) and Example 19(72).

EXAMPLE 23

2′-(4-amidinophenylcarbamoyl)-4-amino-2-biphenylcarboxylic acidmethanesulfonate

TLC:Rf 0.11 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.19(1H, s), 9.13 (2H, brs), 8.88 (2H, brs), 7.73 (2H, d, J=9.0 Hz), 7.63(2H, d, J=9.0 Hz), 7.57 (1H, dd, J=7.0 Hz, 1.5 Hz), 7.51-7.36 (2H, m),7.16 (1H, dd, J=7.0 Hz, 1.5 Hz), 6.98 (1H, d, J=2.0 Hz), 6.85 (1H, d,J=8.0 Hz), 6.62 (1H, dd, J=8.0 Hz, 2.0 Hz), 2.35 (3H, s).

EXAMPLE 23(1)

3-(2′-(4-amidinophenylcarbamoyl)biphenyl-2-yl)propanoic acidmethanesulfonate

TLC:Rf 0.21 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.2-11.9 (1H, broad), 10.55 (1H, s), 9.13 (2H, brs), 8.94 (2H, brs),7.76-7.50 (7H, m), 7.34-7.12 (5H, m), 2.76-2.62 (2H, m), 2.45-2.34 (2H,m), 2.36 (3H, s).

EXAMPLE 24

2′-(4-amidinophenylcarbamoyl)-4-methylcarbonylamino-2-biphenylcarboxylicacid methanesulfonate

To a solution of the compound prepared in Example 23 (376 mg) indimethylformamide (3.2 ml) and pyridine (0.8 ml), acetic acid anhydrous(75.5 μl) was added. The mixture was stirred for 1 hour at roomtemperature. The reaction mixture was concentrated. The residue wascrystallized with ethyl acetate, furthermore, was crystallized withethyl acetate-methanol to give the present compound (407 mg) having thefollowing physical data. TLC:Rf 0.12 (Chloroform:Methanol:Aceticacid=10:2:1); NMR (d₆-DMSO): δ 13.0-12.5 (1H, broad), 10.43 (1H, s),10.12 (1H, s), 9.13 (2H, brs), 8.86 (2H, brs), 8.05 (1H, d, J=2.5 Hz),7.76-7.60 (6H, m), 7.58-7.42 (2H, m), 7.26-7.20 (1H, m), 7.15 (1H, d,J=8.0 Hz), 2.34 (3H, s), 2.04 (3H, s).

EXAMPLE 24(1)-EXAMPLE 24(2)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 24, using compounds prepared in Example 19(102)and Example 23.

EXAMPLE 24(1)

2′-(4-amidinophenylcarbamoyl)-4′-methylcarbonylamino-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.10 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.39 (1H, s), 10.28 (1H, s), 9.19 (2H, brs), 8.96 (2H, brs), 7.89 (1H,d, J=2.0 Hz), 7.80-7.60 (6H, m), 7.49 (1H, td, J=7.5 Hz, 1.5 Hz), 7.37(1H, td, J=7.5 Hz, 1.5 Hz), 7.22 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.17 (1H,d, J=8.0 Hz), 2.35 (3H, s), 2.09 (3H, s).

EXAMPLE 24(2)

2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropylcarbonyl)amino)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.25 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.3-12.2 (1H, broad), 10.43 (1H, s), 10.13 (1H, s), 9.19 (2H, brs),8.98 (2H, brs), 8.10 (1H, d, J=2.5 Hz), 7.78-7.60 (6H, m), 7.56-7.42(2H, m), 7.26-7.19 (1H, m), 7.15 (1H, d, J=8.0 Hz), 2.36 (3H, s), 2.19(2H, d, J=6.5 Hz), 2.15-1.95 (1H, m), 0.92 (6H, d, J=6.5 Hz).

EXAMPLE 25

N-hydroxy-2′-(4-(N²-hydroxyamidino)phenylcarbamoyl)-2-biphenylcarboxamide hydrochloride

1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide (183 mg),1-hydroxybenzotriazole (129 mg) and N-(1-methoxy-1-methylethoxy)amine(333 mg) were added to a solution of the compound prepared in Example19(158) (302 mg) in dimethylformamide (5 ml). The mixture was stirredfor 3 hours at room temperature. The reaction mixture was distilled offan azeotropic mixture with toluene. Methylene chloride (2 ml), methanol(0.5 ml) and 4N hydrochloric acid—dioxane (2 ml) were added to theresidue, and the mixture was stirred for 1 hour at room temperature. Thereaction mixture was concentrated. The residue was purified by columnchromatography on silica gel (Methylene chloride:Methanol:Aceticacid=10:2:1). The purified product was dissolved into methanol (2 ml),and then 4N hydrochloric acid—ethyl acetate (0.16 ml) was added to thesolution. The mixture was concentrated. The obtained compoundhydrochloride was washed with ether to give the present compound (197mg) having the following physical data. TLC:Rf 0.38(Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ 12.79 (1H,br), 11.51 (1H, s), 11.19 (1H, s), 11.2-11.0 (1H, br), 9.4-8.7 (3H, br),7.7-7.4 (8H, m), 7.45-7.35 (2H, m), 7.2-7.0 (2H, m).

EXAMPLE 26

2′-(4-(N²-(2-propenyl)oxycarbonylamidino)phenylcarbamoyl)-2-biphenylcarboxylic acid

The compound prepared in Example 19 (300 mg) was dissolved into a mixedsolution of 2N aqueous solution of sodium hydroxide and tetrahydrofuran(2:1, 15 ml), and then allyloxycarbonyl chloride (140 μl ) was added tothe solution. The mixture was stirred for 30 minutes at roomtemperature. 2N hydrochloric acid (10 ml) was added to the reactionmixture. The precipitate obtained by filtration was washed with water,and dried. The precipitate was crystallized with methanol to give thepresent compound (47 mg) having the following physical data.

TLC:Rf 0.41 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.32(1H, s), 9.10 (2H, br.s), 7.89 (2H, d, J=8.8 Hz), 7.81 (1H, dd,J=1.8,7.8 Hz), 7.66 (1H, m), 7.56 (2H, d, J=8.8 Hz), 7.46-7.54 (3H, m),7.39 (1H, dt, J=1.8,7.8 Hz), 7.21-7.25 (2H, m), 5.96 (1H, m), 5.17-5.35(2H, m), 4.53-4.56 (2H, m).

EXAMPLE 27

t-Butyl 2′-(1-(4-(N²-benzyloxycarbonylamidino)phenylamino)-1-methoxycarbonylmethyl)-2-biphenylcarboxylate

t-Butyl 2′-(1-methoxycarbonyl-1-methylsulfonyloxymethyl)-2-biphenylcarboxylate (3.36 g) and 4-(N²-benzyloxycarbonylamidino)aniline (5.38 g)was dissolved into dimethylformamide (5 ml). The mixture was stirred for19 hours at 60° C., and then for 6 hours at 80° C. After the reactionmixture was cooled to room temperature, water was added to the reactionmixture. The solution was extracted with ethyl acetate. The extract waswashed with water, 0.5 N hydrochloric acid, a saturated aqueous solutionof sodium bicarbonate and a saturated aqueous solution of sodiumchloride, successively, dried over anhydrous sodium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=1:1) to give the title compound (2.03g) having the following physical data.

TLC:Rf 0.53 (Hexane:Ethyl acetate=1:1).

EXAMPLE 27(1)-EXAMPLE 27(2)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 27, using a corresponding compound instead oft-butyl2′-(1-methoxycarbonyl-1-methylsulfonyloxymethyl)-2-biphenylcarboxylate.

EXAMPLE 27(1)

t-Butyl 2′-(1-(4-(N²-benzyoxycarbonylamidino)phenylamino)-1-methylcarbamoylmethyl)-2-biphenylcarboxylate

TLC:Rf 0.36 (Chloroform:Ethyl acetate=1:1); NMR (CDCl₃) δ 10.0-9.0 (2H,broad), 8.0-7.9 (1H, broad), 7.69-7.24 (13H, m), 7.15-7.04 (2H, m), 6.43and 6.23 (2H, d, J=9.0 Hz), 5.70 (0.6H, d, J=2.0 Hz), 5.52 (0.4H, d,J=5.0 Hz), 5.19 (2H, s), 4.89 (0.4H, d, J=5.0 Hz), 4.83 (0.6H, d, J=2.0Hz), 2.92 and 2.63 (3H, d, J=5.0 Hz), 1.41 (9H, s).

EXAMPLE 27(2)

t-Butyl2′-(1-(4-(N²-benzyoxycarbonylamidino)phenylamino)-1-cyanomethyl)-2-biphenylcarboxylate

TLC:Rf 0.79 (Chloroform:Ethyl acetate=7:3); NMR (CDCl₃): δ 7.97-7.09(15H, m), 6.47 and 6.36 (2H, d, J=9.0 Hz), 5.34-5.11 (3H, m), 4.60-4.34(1H, m), 1.37 and 1.22 (9H, s).

REFERENCE EXAMPLE 17

Methyl 2′-ethynyl-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

A solution of potassium t-butoxide (1.43 g) in anhydrous tetrahydrofuran(5 ml) was added to a solution of (bromomethyl)triphenylphosphoniumbromide (2.78 g) in anhydrous tetrahydrofuran (20 ml). The mixture wasstirred for 30 minutes. Methyl2′-formyl-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate (1.8 g)which was prepared by the same procedure as a series of reaction ofReference Example 3 (using 2-methylpropylamine instead of2,2-dimethylpropylamine)→Reference Example 4, using3-methoxycarbonyl-4-trifluoromethylsulfonyloxybenzoic acid; in anhydroustetrahydrofuran (20 ml) was added to the mixture. After the mixture waswarmed to room temperature, it was stirred for 12 minutes. Water (100ml) was added to the reaction mixture, and the solution was extractedwith ethyl acetate. The extract was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=2:1) to give the title compound (1.20g) having the following physical data.

TLC:Rf 0.37 (Hexane:Ethyl acetate=1:1); NMR (CDCl₃): δ 8.32 (1H, d,J=2.0 Hz), 8.01 (1H, dd, J=2.0,8.0 Hz), 7.57 (1H, dd, J=2.0,8.0 Hz),7.43 (1H, d, J=8.0 Hz), 7.42 (1H, dt, J=2.0,8.0 Hz), 7.34 (1H, dt,J=2.0,8.0 Hz), 7.24 (1H, dd, J=2.0,8.0 Hz), 6.30 (1H, br.t, J=6.0 Hz),3.67 (3H, s), 3.33 (2H, t, J=6.0 Hz), 2.91 (1H, s), 1.94 (1H, m), 1.01(6H, d, J=6.6 Hz).

REFERENCE EXAMPLE 18

Methyl2′-(4-cyanophenylethynyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

To a solution of the compound prepared in Reference Example 17 (1.07 g)and p-cyanobromobenzene (640 mg) in dimethylformamide-triethylamine(5:1, 6 ml), dichlorobis(triphenylphosphine)palladium (II) (45 mg) wasadded. The mixture was stirred for 30 minutes 90° C. Water (100 ml) wasadded to the reaction mixture, and the solution was extracted with ethylacetate. The extract was washed with water and a saturated aqueoussolution of sodium chloride, successively, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=2:1→3:2) to give thetitle compound (1.23 g) having the following physical data.

TLC:Rf 0.32 (Hexane:Ethyl acetate=2:1); NMR (CDCl₃): δ 8.38 (1H, d,J=2.0 Hz), 8.03 (1H, dd, J=2.0,8.0 Hz), 7.61 (1H, d, J=8.0 Hz), 7.53(2H, d, J=8.8 Hz), 7.44-7.50 (2H, m), 7.40 (1H, dt, J=2.0,8.0 Hz),7.27-7.34 (3H, m), 6.36 (1H, br.t, J=6.4 Hz), 3.63 (3H, s), 3.34 (2H, t,J=6.4 Hz), 1.95 (1H, m), 1.01 (6H, d, J=6.6 Hz).

EXAMPLE 28

Methyl2′-(4-amidinophenyletynyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

To a solution of the compound prepared in Reference Example 18 (704 mg)in methanol (20 ml), hydrogen chloride gas was introduced below 10° C.The solution was stirred for 12 hours at room temperature. The reactionsolution was concentrated. To a solution of the residue in methanol (20ml), ammonium gas was introduced below 10° C. The solution was stirredfor 12 hours at room temperature. The reaction solution wasconcentrated. The residue was purified by column chromatography onsilica gel (Chloroform:Methanol:Water=9:1:0.1→8:2:0.2) to give thepresent compound (0.41 g) having the following physical data.

TLC:Rf 0.42 (Chloroform:Methanol:Water=8:2:0.2); NMR (CD₃OD): δ 8.45(1H, d, J=2.0 Hz), 8.08 (1H, dd, J=2.0,8.0 Hz), 7.71 (2H, d, J=8.0 Hz),7.52 (1H, d, J=8.0 Hz), 7.53 (1H, t, J=8.0 Hz), 7.50 (1H, t, J=8.0 Hz),7.39-7.46 (4H, m), 3.61 (3H, s), 3.25 (2H, d, J=7.2 Hz), 1.97 (1H, t,J=1.00 (6H, d, J=6.6 Hz).

EXAMPLE 29

Methyl 2′-(4-amidinophenyletynyl)-2-biphenylcarboxyate hydrochloride

The present compound having the following physical data was obtained bythe same procedure as a series of reaction of Reference Example17→Reference Example 18→Example 28, using methyl2′-formyl-2-biphenylcarboxylate.

TLC:Rf 0.41 (Chloroform:Methanol:Acetic acid=20:2:1); NMR (d₆-DMSO): δ9.30 (4H, brs), 7.94 (1H, dd, J=2.0, 8.0 Hz), 7.79 (2H, d, J=8.5 Hz),7.74-7.38 (7H, m), 7.39 (2H, d, J=8.5 Hz), 3.52 (3H, s).

REFERENCE EXAMPLE 19

2′-((1E)-2-(4-cyanophenyl)ethenyl)-4-((2-methylpropyl)carbarmoyl)-2-biphenylcarboxylicacid

A solution of p-tolunitrile (1.7 g) and ethyl2′-formyl-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate (2.58 g)which was prepared by the same procedure as a series of reaction ofReference Example 3 (using 2-methylpropylamine instead of2,2-dimethylpropylamine) Reference Example 4, using3-ethoxycarbonyl-4-trifluoromethylsulfonyloxybenzoic acid; in anhydroushexamethylphosphoramide (3 ml) was added to a solution of potassiumt-butoxide in anhydrous hexamethylphosphoramide (30 ml). The mixture wasstirred for 12 hours at room temperature. The reaction mixture wasdiluted with water (100 ml), and extracted with ethyl acetate. Theextract was washed with water and a saturated aqueous solution of sodiumchloride, successively, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (Chloroform:Methanol=20:1 Chloroform:Methanol:Water=9:1:0.1)to give the title compound (0.96 g) having the following physical data.

TLC:Rf 0.26 (Chloroform:Methanol:Water=9:1:0.1); NMR (CDCl₃): δ 8.40(1H, s), 8.02 (1H, d, J=8.0 Hz), 7.71 (1H, d, J=7.0 Hz), 7.51 (2H, d,J=8.4 Hz), 7.42 (1H, t, J=7.0 Hz), 7.36 (1H, t, J=7.0 Hz), 7.29-7.34(3H, m), 7.16 (1H, d, J=7.0 Hz), 6.95 (1H, d, J=16.0 Hz), 6.85 (1H, d,J=16 Hz), 6.37 (1H, br.t, J=6.6 Hz), 3.32 (2H, t, J=6.6 Hz), 1.94 (1H,m), 1.01 (6H, d, J=6.6 Hz).

EXAMPLE 30

Methyl2′-((1E)-2-(4-amidinophenyl)ethenyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylate

To a solution of the compound prepared in Reference Example 19 (560 mg)in methanol (20 ml), hydrogen chloride gas was introduced below 10° C.The solution was stirred for 12 hours at room temperature. The reactionsolution was concentrated. To a solution of the residue in methanol (20ml), ammonium gas was introduced below 10° C. The solution was stirredfor 12 hours at room temperature. The reaction solution wasconcentrated. The residue was purified by column chromatography onsilica gel (Chloroform:Methanol:Water=9:1:0.1→8:2:0.2) to give thepresent compound (0.41 g) having the following physical data.

TLC:Rf 0.21 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 9.23(2H, s), 8.90 (2H, s), 8.74 (1H, t, J=6.2 Hz), 8.34 (1H, d, J=1.8 Hz),8.13 (1H, dd, J=1.8,8.0 Hz), 7.85 (1H, dd, J=1.8,8.0 Hz), 7.75 (2H, d,J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz), 7.35-7.47 (3H, m), 7.23-7.28 (2H, m),6.90 (1H, d, J=16.2 Hz), 3.46 (3H, s), 3.13 (2H, t, J=6.2 Hz), 2.33 (3H,s), 1.89 (1H, m), 0.92 (6H, d, J=6.6 Hz).

EXAMPLE 31

Methyl 2′-((1E)-2-(4-amidinophenyl)ethenyl)-2-biphenylcarboxylate

The present compound having the following physical data was obtained bythe same procedure as a series of reaction of Reference Example19-Example 30, using ethyl 2′-formyl-2-biphenylcarboxylate. NMR(d₆-DMSO): δ 9.60 (2H, brs), 9.20 (2H, brs), 7.88 (1H, dd, J=1.5, 8.0Hz), 7.84 (1H, dd, J=1.5, 8.0 Hz), 7.73 (2H, d, J=8.5 Hz), 7.60-7.40(2H, m), 7.46 (2H, d, J=8.5 Hz), 7.36 (2H, brt, J=8.0 Hz), 7.30-7.14(2H, m), 7.24 (1H, d, J=16.5 Hz), 6.79 (1H, d, J=16.5 Hz), 3.58 (3H, s).

EXAMPLE 32

Methyl 2-(6-(4-amidinophenylcarbamoyl)isoquinolin-7-yl)benzoate

The present compound having the following physical data was obtained bythe same procedure as a series of reaction of Reference Example4→Reference Example 5→Reference Example 10→Reference Example 12→Example1, using benzyl 7-trifluoromethylsulfonyloxy-6-isoquinolinecarboxylate.

TLC:Rf 0.36 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ9.34 (1H, s), 8.56 (1H, d, J=6.0 Hz), 8.26 (1H, s), 8.04 (1H, s), 8.00(1H, d, J=6.0 Hz), 7.93 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.73 (4H, s), 7.64(1H, td, J=7.5 Hz, 1.5 Hz), 7.52-7.43 (2H, m), 3.61 (3H, s).

EXAMPLE 33-EXAMPLE 33(7)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 19, using a compound prepared inExample 27-Example 32.

EXAMPLE 33

t-Butyl2′-(1-(4-amidinophenylamino)-1-methoxycarbonylmethyl)-2-biphenylcarboxylate

TLC:Rf 0.48 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ7.92-7.83 (1H, m), 7.72-7.10 (9H, m), 6.49-6.39 (2H, m), 4.97 (0.4H, d,J=9.0 Hz), 4.75 (0.6H, d, J=7.5 Hz), 3.57 (3H, s), 1.69 (3H, s), 1.11(5.4H, s), 1.02 (3.6H, s).

EXAMPLE 33(1)

t-Butyl2′-(1-(4-amidinophenylamino)-1-methylcarbamoylmethyl)-2-biphenylcarboxylate

TLC:Rf 0.65 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.83 (0.4H, dd, J=8.0 Hz, 1.5 Hz), 7.65 (0.6H, d, J=8.0 Hz), 7.56-7.08(9H, m), 6.50 and 6.37 (2H, d, J=9.0 Hz), 4.93 and 4.68 (1H, s), 2.80and 2.71 (3H, s), 1.91 (3H, s), 1.32 and 1.27 (9H, s).

EXAMPLE 33(2)

t-Butyl2′-(1-(4-amidinophenylamino)-1-cyanomethyl)-2-biphenylcarboxylate

TLC:Rf 0.48 and 0.55 (Chloroform:Methanol:Acetic acid=10:2:1); NMR(d₆-DMSO): δ 7.85-7.10 (10H, m), 6.69 and 6.56 (2H, d, J=9.0 Hz),5.52-5.14 (1H, m), 1.10 and 1.13 (9H, s).

EXAMPLE 33(3)

2′-(4-amidinophenylethynyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.46 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 12.85(1H, s), 9.33 (2H, s), 9.05 (2H, s), 8.72 (1H, br.t, J=6.4 Hz), 8.44(1H, d, J=1.8 Hz), 8.11 (1H, dd, J=1.8,8.4 Hz), 7.77 (2H, d, J=8.8 Hz),7.63 (1H, 1H, d, J=7.2 Hz), 7.39-7.55 (6H, m), 3.13 (2H, t, J=6.4 Hz),2.35 (3H, s), 1.89 (1H, m), 0.92 (6H, d, J=6.8 Hz).

EXAMPLE 33(4)

2′-(4-amidinophenylethynyl)-2-biphenylcarboxylate acetic acetate

TLC:Rf 0.37 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CDCl₃): δ11.6-9.00 (4H, m), 7.90 (1H, dd, J=2.0, 7.5 Hz), 7.73 (2H, d, J=8.0 Hz),7.54 (1H, brd, J=7.5 Hz), 7.50-7.20 (8H, m), 1.84 (3H, s).

EXAMPLE 33(5)

2′-((1E)-2-(4-amidinophenyl)ethenyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.39 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.78 (1H, s), 9.30 (2H, s), 9.09 (2H, s), 8.75 (1H, br.t, J=6.0 Hz),8.39 (1H, s), 8.09 (1H, d, J=8.0 Hz), 7.87 (1H, d, J=8.0 Hz), 7.77 (2H,d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 7.44 (1H, t, J=8.0 Hz), 7.35-7.41(2H, m), 7.26 (1H, d, J=16.2 Hz), 7.21 (1H, d, J=8.0 Hz), 6.93 (1H, d,J=16.2 Hz), 3.14 (2H, t, J=6.0 Hz), 2.38 (3H, s), 1.90 (1H, m), 0.92(6H, d, J=6.6 Hz).

EXAMPLE 33(6)

2′-((1E)-2-(4-amidinophenyl)ethenyl)-2-biphenylcarboxylic acidtrifluoroacetate

TLC:Rf 0.25 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ9.60 (2H, brs), 9.20 (2H, brs), 7.88 (1H, dd, J=1.5, 8.0 Hz), 7.84 (1H,dd, J=1.5, 8.0 Hz), 7.73 (2H, d, J=8.5 Hz), 7.60-7.40 (2H, m), 7.46 (2H,d, J=8.5 Hz), 7.36 (2H, brt, J=8.0 Hz), 7.30-7.14 (2H, m), 7.24 (1H, d,J=16.5 Hz), 6.79 (1H, d, J=16.5 Hz).

EXAMPLE 33(7)

2-(6-(4-amidinophenylcarbamoyl)isoquinolin-7-yl)benzoic acidmethanesulfonate

TLC:Rf 0.45 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ13.0-12.0 (1H, broad), 10.91 (1H, s), 9.71 (1H, s), 9.20 (2H, brs), 8.94(2H, brs), 8.72 (1H, d, J=6.0 Hz), 8.49 (1H, s), 8.38 (1H, d, J=6.0 Hz),8.26 (1H, s), 7.93 (1H, dd, J=7.5 Hz, 1.5 Hz), 7.78 (2H, d, J=9.0 Hz),7.73 (2H, d, J=9.0 Hz), 7.63 (1H, td, J=7.5 Hz, 1.5 Hz), 7.50 (1H, td,J=7.5 Hz, 1.5 Hz), 7.39 (1H, dd, J=7.5 Hz, 1.5 Hz), 2.34 (3H, s).

EXAMPLE 34-EXAMPLE 34(2)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 19, using a compound prepared inExample 33-Example 33(2).

EXAMPLE 34

2′-(1-(4-amidinophenylamino)-1-methoxycarbonylmethyl)-2-biphenylcarboxylic acid hydrochloride

TLC:Rf 0.39 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.6 (1H, brs), 8.81 (2H, brs), 8.55 (2H, brs), 7.99-7.87 (1H, m),7.70-7.10 (9H, m), 6.52 and 6.47 (2H, d, J=9.0 Hz), 4.94 and 4.76 (1H,d, J=7.0 Hz), 3.55 (3H, s).

EXAMPLE 34(1)

2′-(1-(4-amidinophenylamino)-1-methylcarbamoylmethyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.30 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.90 (0.4H, dd, J=8.0 Hz, 2.0 Hz), 7.74 (0.6H, dd, J=8.0 Hz, 1.0 Hz),7.54-7.08 (9H, m), 6.48 (0.8H, d, J=9.0 Hz), 6.39 (1.2H, d, J=9.0 Hz),4.84 (0.6H, s), 4.81 (0.4H, s), 2.79 (1.8H, s), 2.71 (3H, s), 2.68(1.2H, s).

EXAMPLE 34(2)

2′-(1-(4-amidinophenylamino)-1-cyanomethyl)-2-biphenylcarboxylic acidhydrochloride

TLC:Rf 0.28 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ7.86-7.11 (10H, m), 6.61 (2H, d, J=8.0 Hz), 5.50 and 5.43 (1H, s).

EXAMPLE 35

2′-(1-(4-amidinophenylamino)-1-carboxymethyl)-2-biphenylcarboxylic acidhydrochloride

The present compound having the following physical data was obtained bythe same procedure as a series of reaction of Reference Example 19,using a compound prepared in Example 34.

TLC:Rf 0.09 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.8-11.6 (1H, broad), 8.81 and 8.87 (2H, brs), 8.70 (2H, brs),7.95-7.86 (1H, m), 7.65-7.30 (7H, m), 7.25-7.11 (2H, m), 6.48 and 6.45(2H, d, J=8.5 Hz), 4.83 and 4.65 (1H, s).

EXAMPLE 36-EXAMPLE 36(1)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 2, using a compound prepared in Example 33(3) andExample 33(4).

EXAMPLE 36

2′-(2-(4-amidinophenyl)ethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.46 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 12.83(1H, s), 9.19 (2H, s), 9.02 (2H, s), 8.71 (1H, br.t, J=6.8 Hz), 8.35(1H, d, J=2.0 Hz), 8.03 (1H, dd, J=2.0,8.0 Hz), 7.64 (2H, d, J=8.0 Hz),7.16-7.31 (6H, m), 7.06 (1H, d, J=8.0 Hz), 3.12 (2H, t, J=6.8 Hz),2.61-2.77 (4H, m), 2.33 (3H, s), 1.88 (1H, m), 0.92 (6H, d, J=7.0 Hz).

EXAMPLE 36(1)

2′-(2-(4-amidinophenyl)ethyl)-2-biphenylcarboxylic acid acetate

TLC:Rf 0.42 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CDCl₃): δ11.6-9.80 (2H, m), 9.80-8.00 (1H, m), 7.79 (1H, dd, J=2.0, 7.5 Hz), 7.59(2H, d, J=8.0 Hz), 7.40-7.30 (2H, m), 7.22-7.10 (5H, m), 7.10-7.00 (2H,m), 1.84 (3H, s).

REFERENCE EXAMPLE 20

4-(2′-methoxycarbonylbiphenyl-2-yloxymethyl)phenylmethylthioimidatehydroiodide

To a solution of methyl 2′-(4-cyanobenzyloxy)-2-biphenylcarboxylate(2.14 g) which was prepared by the same procedure as a series ofreaction of Example 16 (using 4-cyanobenzyl bromide instead of acompound prepared in Reference Example 16, and using 2-bromophenolinstead of 4-amidinoaniline)→Reference Example 4→Reference Example5→Reference Example 14; in dimethylformamide (40 ml), magnesium chloridehexahydroxide (1.39 mg) and sodium hydrogensulfide (629 mg) was added.The mixture was stirred for 4 hours at room temperature. The reactionmixture was diluted with ethyl acetate (100 ml), and the solution waswashed with a saturated aqueous solution of sodium chloride (50 ml, 2times). The organic layer was dried over anhydrous sodium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=3:1) to give thioamide compound (2.74g). Thioamide compound (2.74 g) was dissolved into acetone (50 ml), andthen methyl iodide (1.94 ml) was added to the solution at roomtemperature. The mixture was refluxed for 1 hour. The reaction mixturewas concentrated to give the title compound (3.42 g) having thefollowing physical data.

TLC:Rf 0.69 (Chloroform:Methanol=10:1); NMR (CDCl₃): δ 8.01 (2H, d,J=8.5 Hz), 7.94 (1H, dd, J=1.5, 7.5 Hz), 7.58 (1H, dt, J=1.5, 7.5 Hz),7.44 (1H, dt, J=1.5, 7.5 Hz), 7.38 (2H, d, J=8.5 Hz), 7.4-7.25 (5H, m),7.09 (1H, dt, J=1.5, 7.5 Hz), 6.90 (1H, br.d, J=7.5 Hz), 5.07 (2H, s),3.60 (3H, s), 3.13 (3H, s).

EXAMPLE 37

Methyl 2′-(4-amidinobenzyloxy)-2-biphenylcarboxylate

The compound prepared in Reference Example 20 (3.23 g) and ammoniumacetate (959 mg) was dissolved into ethanol (50 ml). The mixture wasrefluxed for 1 hour. The reaction mixture was cooled to roomtemperature, and concentrated. The residue was purified by columnchromatography on silica gel(Chloroform:Methanol=10:1→Chloroform:Methanol:Water=10:2:0.1) to givethe present compound (2.15 g) having the following physical data.

TLC:Rf 0.38 (Chloroform:Methanol:Acetic acid=10:1:0.2); NMR (d₆-DMSO): δ9.4-8.83 (4H, br), 7.80 (1H, dd, J=1.0, 8.0 Hz), 7.73 (2H, d, J=8.4 Hz),7.63 (1H, dt, J=1.0, 8.0 Hz), 7.48 (1H, dt, J=1.0, 8.0 Hz), 7.42 (2H, d,J=8.4 Hz), 7.4-7.25 (2H, m), 7.21 (1H, dd, J=1.0, 8.0 Hz), 7.1-7.0 (2H,m), 5.15 (2H, s), 3.52 (3H, s).

EXAMPLE 38

2′-(4-amidinobenzyloxy)-2-biphenylcarboxylic acid methanesulfonate

The present compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 19, using thecompound prepared in Example 37.

TLC:Rf 0.60 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.46 (1H, br.s), 9.24 (2H, s), 8.91 (2H, s), 7.82 (1H, dd, J=1.0, 7.5Hz), 7.72 (2H, d, J=8.4 Hz), 7.58 (1H, dt, J=1.0, 7.5 Hz), 7.5-7.4 (1H,m), 7.46 (2H, d, J=8.4 Hz), 7.35-7.25 (2H, m), 7.18 (1H, dd, J=1.0, 7.5Hz), 7.05-6.95 (2H, m), 5.15 (2H, s), 2.31 (3H, s).

REFERENCE EXAMPLE 21

Benzyl 2′-(tetrazol-5-yl)-2-biphenylcarboxylate

To a solution of benzyl 2′-cyano-2-bipheylcarboxylate (560 mg) intoluene (10 ml), azidotrimethyltin (810 mg) was added. The mixture wasrefluxed for 12 hours. The reaction mixture was concentrated. 5% aqueoussolution of potassium fluoride (4 ml) was added to the residue. Thesolution was filtered. The filtrate was diluted with ethyl acetate, andthe solution was washed with a saturated aqueous solution of sodiumchloride. The organic layer was dried over anhydrous sodium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=2:1→chloroform:methanol=10:1) to givethe title compound (545 mg) having the following physical data.

TLC:Rf 0.08 (Hexane:Ethyl acetate=2:1).

REFERENCE EXAMPLE 22

Benzyl 2′-(triphenylmethyltetrazol-5-yl)-2-biphenylcarboxylate

Triethylamine (2.74 ml) and trityl chloride (549 mg) were added to asolution of the compound prepared in Reference Example 21 (545 mg) inmethylene chloride (10 ml). The mixture was stirred for 1 hour at roomtemperature. The reaction mixture was diluted with chloroform (50 ml),and the solution was washed with water (50 ml). The organic layer wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=8:1) to give the title compound (713 mg) having the followingphysical data.

TLC:Rf 0.71 (Hexane:Ethyl acetate=2:1).

EXAMPLE 39

2′-(4-amidinophenylcarbamoyl)-2-(tetrazol-5-yl)biphenyl methanesulfonate

The present compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 11→Example1→Example 2, using a compound prepared in Reference Example 22.

TLC:Rf 0.35 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.32 (1H, s), 9.14 (2H, s), 8.80 (2H, s), 7.71 (2H, d, J=9.0 Hz),7.7-7.45 (6H, m), 7.63 (2H, d, J=9.0 Hz), 7.42 (1H, dd, J=1.2, 7.5 Hz),7.24 (1H, dd, J=1.2, 7.5 Hz), 4.2-3.5 (1H, br), 2.32 (3H, s).

REFERENCE EXAMPLE 23

Benzyl4′-benzyloxycarbonylamino-2′-methoxymethyloxycarbonyl-4-hydroxymethyl-2-biphenylcarboxylate

To a solution of benzyl4′-benzyloxycarbonylamino-2′-methoxymethyloxycarbonyl-4-t-butyidiphenylsilyloxymethyl-2-biphenylcarboxylate (777 mg) which was prepared by the same procedure as aseries of reaction of Reference Example 6→Reference Example 1 (withoutan esterfication of benzyl)→Reference Example 4→Reference Example5→Reference Example 7, using 5-benzyloxycarbonylaminosalicylic acid; inanhydrous tetrahydrofuran (10 ml), a solution of 1.0 Mtetrabutylammonium fluoride in anhydrous tetrahydrofuran (1.0 ml) wasadded. The mixture was stirred for 2 hours at room temperature. Water(100 ml) was added to the reaction mixture, the solution was extractedwith ethyl acetate. The organic layer was washed with a saturatedaqueous solution of sodium chloride, successively, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=2:3) to give thetitle compound (370 mg) having the following physical data.

TLC:Rf 0.29 (n-Hexane:Ethyl acetate=1:1); NMR (200 MHz, CDCl₃): δ 8.02(d, J=2.0 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.65 (dd, J=8.0,2.0 Hz, 1H),7.54 (dd, J=8.0,2.0 Hz, 1H), 7.45-7.38 (m, 5H), 7.28-7.07 (m, 7H), 6.78(s, 1H), 5.25 (s, 2H), 5.16 (d, J=6.0 Hz, 1H), 5.10 (d, J=6.0 Hz, 1H),5.04 (s, 2H), 4.76 (s, 2H), 3.21 (s, 3H).

REFERENCE EXAMPLE 24

Benzyl4′-benzyloxycarbonylamino-2′-methoxymethyloxycarbonyl-4-formyl-2-biphenylcarboxylate

Dimethylsulfoxide (124 μl) was added to a solution of oxalyl chloride(120 μl) in anhydrous methylene chloride (5 ml) at −78° C. The mixturewas stirred for 10 minutes. The compound prepared in Reference Example23 (370 mg) in anhydrous methylene chloride (5 ml) was added to theabove solution at −78° C. The mixture was stirred for 1 hour.Triethylamine (0.38 ml) was added to the reaction mixture at −78° C. Themixture was stirred for 1 hour at room temperature. Water (50 ml) wasadded to the reaction mixture at −78 ° C. The solution was extractedwith ethyl acetate. The organic layer was washed with a saturatedaqueous solution of sodium chloride, successively, dried over anhydrousmagnesium sulfate and concentrated to give the title compound (356 mg)having the following physical data.

TLC:Rf 0.65 (n-Hexane:Ethyl acetate=1:1); NMR (200 MHz, CDCl₃): δ 10.09(s, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.04 (dd, J=8.0,2.0 Hz, 1H), 7.86 (d,J=2.0 Hz, 1H), 7.71 (dd, J=8.0,2.0 Hz, 1H), 7.46-7.35 (m, 5H), 7.26-7.24(m, 4H), 7.17-7.08 (m, 3H), 6.75 (s, 1H), 5.26 (s, 2H), 5.16 (d, J=6.4Hz, 1H), 5.12 (d, J=6.4 Hz, 1H), 5.08 (s, 2H), 3.25 (s, 3H).

REFERENCE EXAMPLE 25

Benzyl2-(2-formyl-6-methoxy-3-pyridyl)-5-((1(S)-t-butyldimethylsilyloxymethyl-2,2-dimethylpropyl)carbamoyl)benzoate

To a solution of 3-tributyltin-2-formyl-6-methoxypyridine (2.45 g) andbenzyl2-trofluoromethylsulfonyloxy-5-((1(R)-t-butylmethylsilyloxymethyl-2,2-dimethylpropyl)carbamoyl)benzoate(2.36 g) which was prepared by the same procedure as a series ofreaction of Reference Example 1 Reference Example 2→Reference Example 3,using a corresponding compound; in dimethylformamide (15 ml), copperoxide (II) (305 mg) and dichlorobis(triphenylphosphine)palladium (II)(134 mg) were added. The mixture was stirred for 1 hour at 110° C. Thereaction mixture was cooled to room temperature, and ethyl acetate andwater were added to the reaction solution. Insoluble solid was removedby filtration. The filtrate was extracted. The organic layer was washedtwo times with water, and a saturated aqueous solution of sodiumchloride, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=7:3) to give the present compound (2.02 g) havingthe following physical data.

TLC:Rf 0.51 (Hexane:Ethyl acetate=7:3); NMR (300 MHz, CDCl₃): δ 9.78 (s,1H), 8.49 and 8.46 (d, J=2.0 Hz, 1H), 8.00 and 7.97 (dd, J=8.0, 2.0 Hz,1H), 7.39 (d, J=8.0 Hz, 1H), 7.32-7.27 (m, 4H), 7.19-7.12 (m, 2H), 6.87(d, J=8.0 Hz, 1H), 6.63 (d, J=9.6 Hz, 1H), 5.08 (2H, m), 4.06-4.00 (m,1H), 4.03 (s, 3H), 3.91 (dd, J=10.5, 3.3 Hz, 1H), 3.76 (dd, J=10.5, 4.5Hz, 1H), 1.04 (s, 9H), 0.88 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H).

EXAMPLE 40(1)-40(88)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 1, using a compound prepared by the sameprocedure as a series of reaction of Reference Example 1→ReferenceExample 2→Reference Example 3→Reference Example 4 or Reference Example25→Reference Example 5 using a corresponding compound instead of acompound prepared in Reference Example 5, or using a compound preparedby the same procedure as a series of reaction of Reference Example5→Reference Example 3→Example 4 using the compound prepared in ReferenceExample 24 or a compound prepared by the same procedure as it, and usinga corresponding compound instead of 4-amidinoaniline.

EXAMPLE 40(1)

Benzyl 2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1,2,2-trimethylpropyl)carbamoyl]benzoate

TLC:Rf 0.27 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (200 MHz,CD₃OD): δ 8.64 (1H, d, J=5.0 Hz), 8.50 (1H, s), 8.39 (1H, d, J=2.0 Hz),8.00 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.70 (4H, s), 7.61 (1H, d, J=5.0 Hz),7.47 (1H, d, J=8.0 Hz), 7.30-7.23 (3H, m), 7.23-7.13 (2H, m), 5.11 (2H,s), 4.05 (1H, q, J=7.0 Hz), 1.16 (3H, d, J=7.0 Hz), 0.96 (9H, s).

EXAMPLE 40(2)

Benzyl 2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(2-methylpropyl)carbamoyl]benzoate

TLC:Rf 0.49 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.52 (1H, d, J=2.0 Hz), 8.03 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.85(2H, d, J=9.0 Hz), 7.76 (2H, d, J=9.0 Hz), 7.55 (1H, d, J=7.5 Hz), 7.43(1H, d, J=7.5 Hz), 7.32 (1H, d, J=8.0 Hz), 7.27-7.16 (3H, m), 7.09-7.03(2H, m), 5.04 (1H, brd, J=12 Hz), 4.98 (1H, brd, J=12 Hz), 3.23 (2H, d,J=7.0 Hz), 2.64 (3H, s), 2.03-1.88 (1H, m), 0.98 (6H, d, J=6.5 Hz).

EXAMPLE 40(3)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1,2,2-trimethylpropyl)carbamoyl]benzoate

TLC:Rf 0.51 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.48 (1H, d, J=2.0 Hz), 8.00 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.85(2H, d, J=9.0 Hz), 7.76 (2H, d, J=9.0 Hz), 7.56 (1H, d, J=8.0 Hz), 7.43(1H, d, J=8.0 Hz), 7.32 (1H, d, J=8.0 Hz), 7.28-7.16 (3H, m), 7.10-7.06(2H, m), 5.05 (1H, brd, J=12 Hz), 4.98 (1H, brd, J=12 Hz), 4.10 (1H, q,J=7.0 Hz), 2.64 (3H, s), 1.20 (3H, d, J=7.0 Hz), 1.00 (9H, s).

EXAMPLE 40(4)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-(1,1-dimethylpropylcarbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.39 (Chloroform:Methanol:Water=8:2:0.1); NMR (300 MHz, CD₃OD): δ8.21 (d, J=1.8 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H), 7.67 (d, J=9.0 Hz,2H), 7.68-7.64 (m, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.56-7.46 (m, 2H), 7.39(d, J=7.8 Hz, 1H), 7.28-7.24 (m, 4H), 7.16-7.13 (m, 2H), 5.12 (s, 2H),1.85 (q, J=7.5 Hz, 2H), 1.38 (s, 6H), 0.88 (t, J=7.5 Hz, 3H).

EXAMPLE 40(5)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-[(1(S)-t-butyl-2-methoxycarbonylethyl)carbamoyl]-2-biphenylcarboxylate

TLC:Rf 0.37 (Chloroform:Methanol:Water=8:2:0.1); NMR (200 MHz, CD₃OD): δ8.25 (d, J=1.8 Hz, 1H), 7.92 (dd, J=8.0, 1.8 Hz, 1H), 7.70-7.49 (m, 7H),7.42 (d, J=7.8 Hz, 1H), 7.29-7.25 (m, 4H), 7.18-7.15 (m, 2H), 5.12 (s,2H), 4.39 (dd, J=11.4,3.2 Hz, 1H), 3.56 (s, 3H), 2.72 (dd, J=14.6, 3.2Hz, 1H), 2.53 (dd, J=14.6, 11.4 Hz, 1H), 0.97 (s, 9H).

EXAMPLE 40(6)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethylcyclohexylcarbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.75 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.65 (1H, s), 9.3-8.8 (3H, br), 8.21 (1H, d, J=1.5 Hz), 8.13 (1H, d,J=9.0 Hz), 8.01 (1H, dd, J=8.0, 1.5 Hz), 7.75 (4H, like s), 7.70 (1H,dd, J=8.0, 1.5 Hz), 7.6-7.5 (2H, m), 7.38 (1H, d, J=8.0 Hz), 7.35-7.20(4H, m), 7.10-7.00 (2H, m), 5.03 (2H, br.s), 3.79 (1H, m), 1.8-1.6 (1H,m), 1.6-1.3 (4H, m), 1.4-1.2 (3H, m), 0.89 (3H, s), 0.83 (3H, s).

EXAMPLE 40(7)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-(1-isopropyl-2-methylpropylcarbamoyl)-2-biphenylcarboxylate

TLC:RF 0.41 (Chloroform:Methanol:Water 8:2:0.2); NMR (200 MHz, CD₃OD): δ8.31 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.0,2.0 Hz, 1H), 7.70-7.59 (m, 5H),7.55-7.50 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.29-7.26 (m, 4H), 7.18-7.13(m, 2H), 5.14 (s, 2H), 3.72 (t, J=7.0 Hz, 1H), 1.95 (m, 2H), 0.95 (d,J=7.0 Hz, 6H), 0.90 (d, J=7.0 Hz, 6H).

EXAMPLE 40(8)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-[(4,4-dimethyloxolan-3(S)-yl)carbamoyl]-2-biphenylcarboxylic acid

TLC:Rf 0.31 (Chloroform:Methanol:Water=8:2:0.1); NMR (200 MHz, CD₃OD): δ8.31 (d, J=1.8 Hz, 1H), 7.98 (dd, J=8.0, 1.8 Hz, 1H), 7.71-7.59 (m, 6H),7.59-7.49 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.28-7.25 (m, 3H), 7.16-7.11(m, 2H), 5.12 (s, 2H), 4.44 (dd, J=7.4, 5.4 Hz, 1H), 4.20 (dd, J=9.2,7.4 Hz, 1H), 3.72 (dd, J=9.2, 5.4 Hz, 1H), 3.63-3.53 (m, 2H), 1.16 (s,3H), 1.02 (s, 3H).

EXAMPLE 40(9)

Benzyl 2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(2-methylpropyl)carbamoyl]benzoate

TLC:Rf 0.62 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,d₆-DMSO): δ 10.98 (s, 1H), 9.4-9.0 (br, 3H), 8.76 (br.t, J=6.6 Hz, 1H),8.70 (dd, J=4.5, 1.8 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.11 (dd, J=7.8,1.8 Hz, 1H), 7.93 (d, J=8.7 Hz, 2H), 7.85-7.75 (m, 1H), 7.79 (d, J=8.7Hz, 2H), 7.68 (dd, J=7.8, 4.5 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.3-7.15(m, 3H), 7.15-7.05 (m, 2H), 5.02 (s, 2H), 3.11 (t, J=6.6 Hz, 2H), 1.87(like septet, J=6.6 Hz, 1H), 0.90 (d, J=6.6 Hz, 6H).

EXAMPLE 40(10)

Benzyl 2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(3-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoate

TLC:Rf 0.44 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD) δ 8.52 (d, J=2.0 Hz, 1H), 8.04 (dd, J=8.0, 2.0 Hz, 1H), 7.85 (d,J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.43 (d,J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.27-7.16 (m, 3H), 7.09-7.03 (m,2H), 5.04 (d, J=12 Hz, 1H), 4.98 (d, J=12 Hz, 1H), 3.34 (s, 2H),3.33-3.30 (m, 2H), 2.64 (s, 3H), 0.96 (s, 6H).

EXAMPLE 40(11)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1,2,2-trimethylpropyl)carbamoyl]benzoate

TLC:Rf 0.77 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.98 (1H, s), 9.3-8.8 (3H, br), 8.71 (1H, dd, J=4.2, 1.2 Hz), 8.38 (1H,d, J=1.2 Hz), 8.27 (1H, br.d, J=9.0 Hz), 8.09 (1H, dd, J=7.8, 1.2 Hz),7.93 (2H, d, J=8.7 Hz), 7.8-7.75 (3H, m), 7.69 (1H, dd, J=7.8, 4.2 Hz),7.38 (1H, d, J=7.8 Hz), 7.3-7.15 (3H, m), 7.15-7.05 (2H, m), 5.03 (2H,s), 4.00 (1H, m), 1.10 (3H, d, J=6.4 Hz), 0.92 (9H, s).

EXAMPLE 40(12)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-[(1 (R),2,2-trimethylpropyl)carbamoyl]-2-biphenylcarboxylate

TLC:Rf 0.30 (Chloroform:Methanol:Water=8:2:0.1); NMR (200 MHz, CD₃OD): δ8.27 (d, J=2.0 Hz, 1H), 7.94 (dd, J=8.2, 2.0 Hz, 1H), 7.70-7.58 (m, 5H),7.55-7.49 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.29-7.25 (m, 4H), 7.17-7.12(m, 2H), 5.12 (s, 2H), 4.10-3.99 (m, 1H), 1.15 (d, J=7.0 Hz, 3H), 0.95(s, 9H).

EXAMPLE 40(13)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-[(1(S),2,2-trimethylpropyl)carbamoyl]-2-biphenylcarboxylate

TLC:Rf 0.30 (Chloroform:Methanol:Water=8:2:0.1); NMR (200 MHz, CD₃OD): δ8.27 (d, J=2.0 Hz, 1H), 7.94 (dd, J=8.2, 2.0 Hz, 1H), 7.70-7.58 (m, 5H),7.55-7.49 (m, 2H), 7.44 (d, J=8.2 Hz, 1H), 7.29-7.25 (m, 4H), 7.17-7.12(m, 2H), 5.13 (s, 2H), 4.10-3.99 (m, 1H), 1.15 (d, J=6.8 Hz, 3H), 0.95(s, 9H).

EXAMPLE 40(14)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(2,2-dimethylpropyl)carbamoyl]benzoate

TLC:Rf 0.56 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.51 (d, J=2.0 Hz, 1H), 8.03 (dd, J=8.0, 2.0 Hz, 1H), 7.85 (d,J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.43 (d,J=7.8 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.28-7.16 (m, 3H), 7.09-7.04 (m,2H), 5.04 (d, J=12 Hz, 1H), 4.98 (d, J=12 Hz, 1H), 3.25 (s, 2H), 2.64(s, 3H), 0.99 (s, 9H).

EXAMPLE 40(15)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-methylpropyl)carbamoyl]benzoicacid

TLC:Rf 0.58 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.51 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.0, 2.0 Hz, 1H), 7.83 (d,J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.54 (d, J=8.4 Hz, 1H), 7.31 (d,J=8.0 Hz, 1H), 7.28-7.16 (m, 3H), 7.10-7.04 (m, 2H), 6.98 (d, J=8.4 Hz,1H), 1H), 5.07 (brd, J=12 Hz, 1H), 4.98 (brd, J=12 Hz, 1H), 4.06 (s,3H), 3.23 (d, J=6.8 Hz, 2H), 2.03-1.88 (m, 1H), 0.98 (d, J=6.8 Hz, 6H).

EXAMPLE 40(16)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-(1-methoxycarbonylcyclopentylcarbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.40 (Chloroform:Methanol:Water=8:2:0.1); NMR (200 MHz, CD₃OD): δ8.30 (d, J=1.8 Hz, 1H), 7.97 (dd, J=8.0, 1.8 Hz, 1H), 7.70-7.62 (m, 5H),7.55-7.48 (m, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.28-7.22 (m, 4H), 7.17-7.12(m, 2H), 5.12 (s, 2H), 3.68 (s, 3H), 2.36-2.21 (m, 2H), 2.13-2.00 (m,2H), 1.86-1.75 (m, 4H).

EXAMPLE 40(17)

Benzyl2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-hydroxymethyl-2-methylpropyl)carbamoyl]benzoate

TLC:Rf 0.22 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.63 (d, J=5.1 Hz, 1H), 8.50 (d, J=1.0 Hz, 1H), 8.45 (d, J=2.0Hz, 1H), 8.06 (dd, J=8.0, 2.0 Hz, 1H), 7.71 (d, J=9.0 Hz, 2H), 7.67 (d,J=9.0 Hz, 2H), 7.60 (dd, J=5.1, 1.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H),7.30-7.26 (m, 3H), 7.20-7.16 (m, 2H), 5.14 (brd, J=12 Hz, 1H), 5.09(brd, J=12 Hz, 1H), 3.91 (ddd, J=6.9, 6.6, 4.2 Hz, 1H), 3.73 (dd,J=11.4, 4.2 Hz, 1H), 3.65 (dd, J=11.4, 6.6 Hz, 1H), 2.05-1.94 (m, 1H),1.00 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.9 Hz, 3H).

EXAMPLE 40(18)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1(S)-hydroxymethyl-2-methylpropyl)carbamoyl]benzoate

TLC:Rf 0.43 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.54 (d, J=2.0 Hz, 1H), 8.05 (dd, J=8.0, 2.0 Hz, 1H), 7.85 (d,J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.43 (d,J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.28-7.16 (m, 3H), 7.10-7.03 (m,2H), 5.04 (brd, J=12 Hz, 1H), 4.98 (brd, J=12 Hz, 1H), 3.96 (ddd, J=6.9,6.6, 4.2 Hz, 1H), 3.76 (dd, J=11.4, 4.2 Hz, 1H), 3.70 (dd, J=11.4, 6.6Hz, 1H), 2.64 (s, 3H), 2.09-1.93 (m, 1H), 1.03 (d, J=6.6 Hz, 3H), 1.00(d, J=6.9 Hz, 3H).

EXAMPLE 40(19)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-hydroxymethyl-2-methylpropyl)carbamoyl]benzoate

TLC:Rf 0.83 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d6-DMSO): δ10.97 (s, 1H), 9.3-8.8 (br, 3H), 8.71 (dd, J=4.4, 2.1 Hz, 1H), 8.42 (d,J=2.1 Hz, 1H), 8.28 (d, J=9.6 Hz, 1H), 8.13 (dd, J=8.0, 2.1 Hz, 1H),7.94 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.8-7.7 (m, 1H), 7.68(dd, J=8.0, 4.4 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.3-7.2 (m, 3H),7.15-7.0 (m, 2H), 5.02 (s, 2H), 4.61 (t, J=5.5 Hz, 1H), 3.83 (m, 1H),3.53 (t, J=5.5 Hz, 2H), 1.90 like sextet, J=6.6 Hz, 1H), 0.92 (d, J=6.6Hz, 3H), 0.88 (d, J=6.6 Hz, 3H).

EXAMPLE 40(20)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-[(2-methoxycarbonyl-2,2-dimethylethyl)carbamoyl]-2-biphenylcarboxylate

TLC:Rf 0.49 (Chloroform:Methanol:Water=8:2:0.1); NMR (200 MHz, CDCl₃): δ8.27 (d, J=2.0 Hz, 1H), 7.95 (dd, J=8.0,2.0 Hz, 1H), 7.70-7.58 (m, 5H),7.55-7.49 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.30-7.22 (m, 4H), 7.17-7.12(m, 2H), 5.12 (s, 2H), 3.64 (s, 3H), 3.52 (s, 2H), 1.21 (s, 6H).

EXAMPLE 40(21)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1(S)-methoxycarbonyl-2-methylpropyl)carbamoyl]benzoate

TLC:Rf 0.71 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.52 (d, J=2.0 Hz, 1H), 8.05 (dd, J=8.0, 2.0 Hz, 1H), 7.85 (d,J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.43 (d,J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.26-7.16 (m, 3H), 7.10-7.06 (m,2H), 5.04 (brd, J=12 Hz, 1H), 4.98 (brd, J=12 Hz, 1H), 4.52 (d, J=6.9Hz, 1H), 3.76 (s, 3H), 2.64 (s, 3H), 2.34-2.23 (m, 1H), 1.06 (d, J=6.3Hz, 3H), 1.04 (d, J=6.6 Hz, 3H).

EXAMPLE 40(22)

Benzyl2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-methoxycarbonyl-2-methylpropyl)carbamoyl]benzoate

TLC:Rf 0.63 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.64 (d, J=5.0 Hz, 1H), 8.51 (s, 1H), 8.44 (d, J=2.0 Hz, 1H),8.06 (dd, J=8.0, 2.0 Hz, 1H), 7.71 (d, J=9.0 Hz, 2H), 7.67 (d, J=9.0 Hz,2H), 7.60 (d, J=5.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.30-7.24 (m, 3H),7.20-7.14 (m, 2H), 5.14 (brd, J=12 Hz, 1H), 5.10 (brd, J=12 Hz, 1H),4.47 (d, J=7.0 Hz, 1H), 3.74 (s, 3H), 2.31-2.19 (m, 1H), 1.02 (d, J=6.6Hz, 3H), 1.00 (d, J=6.9 Hz, 3H).

EXAMPLE 40(23)

Benzyl2′-(4-amidino-3-benzyloxyphenylcarbamoyl)-4-(2-methylpropylearbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.31 (Chloroform:Methanol:Water=8:2:0.2); NMR (200 MHz, CD₃OD): δ8.34 (d, J=2.0 Hz, 1H), 7.98 (dd, J=8.0, 2.0 Hz, 1H), 7.67 (dd,J=8.0,2.0 Hz, 1H), 7.55-7.24 (m, 14H), 7.17-7.12 (m, 2H), 7.01 (dd,J=8.0,2.0 Hz, 1H), 5.12 (s, 2H), 5.10 (s, 2H), 3.18 (d, J=7.0 Hz, 2H),1.91 (m, 1H), 0.95 (d, J=6.6 Hz, 6H).

EXAMPLE 40(24)

Benzyl2′-(4-amidino-3-benzyloxyphenylcarbamoyI)-4-(1,2,2-trimethylpropylcarbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.38 (Chloroform:Methanol:Water=8:2:0.2); NMR (300 MHz, CD₃OD): δ8.31 (d, J=2.0 Hz, 1H), 8.17 (br.d, J=9.0 Hz, 1H), 7.95 (dd, J=8.0,2.0Hz, 1H), 7.66 (dd, J=8.0,2.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.54-7.50(m, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.43-7.31 (m, 5H), 7.29-7.24 (m, 4H),7.15-7.12 (m, 2H), 7.02 (d, J=8.0 Hz, 1H), 5.10 (s, 4H), 4.06 (m, 1H),1.16 (d, J=7.0 Hz, 3H), 0.96 (s, 9H).

EXAMPLE 40(25)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-(1,3-dimethylbutylcarbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.30 (Chloroform:Ethyl acetate:Water=8:2:0.2); NMR (300 MHz,CD₃OD): δ 8.30 (d, J=2.0 Hz, 1H), 7.95 (dd, J=8.1, 2.0 Hz, 1H),7.69-7.65 (m, 4H), 7.62-7.59 (m, 2H), 7.52 (m, 2H), 7.41 (d, J=8.1 Hz,1H), 7.28-7.26 (m, 3H), 7.17-7.14 (m, 2H), 5.13 (s, 2H), 4.22 (m, 1H),1.70-1.52 (m, 2H), 1.25 (m, 1H), 1.19 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6Hz, 6H).

EXAMPLE 40(26)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethyl-1(R)-cyclopentylcarbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.50 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.28 (d, J=1.8 Hz, 1H), 7.95 (dd, J=7.8, 1.8 Hz, 1H),7.70-7.58 (m, 5H), 7.53 (td, J=6.0, 1.8 Hz, 1H), 7.50 (td, J=6.0, 1.8Hz, 1H), 7.41 (d, J=7.8 Hz, 1H, 7.30-7.22 (m, 4H), 7.18-7.12 (m, 2H),5.12 (s, 2H), 4.17 (q, J=7.8 Hz, 1H), 2.08-1.98 (m, 1H), 1.80-1.52 (m,5H), 1.05 (s, 3H), 0.93 (s, 3H).

EXAMPLE 40(27)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-carboxy-2-methylpropyl)carbamoyl]benzoate

TLC:Rf 0.73 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ810.40 (1H, br.s), 9.10 (3H, br.s), 8.97 (1H, br.s, J=7.5 Hz), 8.71 (1H,dd, J=4.5, 1.5 Hz), 8.43 (1H, d, J=1.5 Hz), 8.14 (1H, dd, J=8.0, 1.5Hz), 7.94 (2H, d, J=9.0 Hz), 7.78 (2H, d, J=9.0 Hz), 7.8-7.7 (1H, m),7.69 (1H, dd, J=7.5, 4.5 Hz), 7.41 (1H, d, J=8.0 Hz), 7.4-7.3 (5H, m),7.25-7.15 (3H, m), 7.15-7.05 (2H, m), 5.20 (1H, d, J=12.6 Hz), 5.14 (1H,d, J=12.6 Hz), 5.03 (2H, s), 4.37 (1H, t, J=7.5 Hz), 2.23 (1H, m), 0.99(3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz).

EXAMPLE 40(28)

Benzyl2-[3-(4-amidinophenylcarbamoyl)-2-furyl]-5-(2-methylpropylcarbamoyl)benzoate

TLC:Rf 0.61 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,DMSO-d₆): δ 8.38 (d, J=2.0 Hz, 1H), 8.04 (dd, J=8.0, 2.0 Hz, 1H), 7.85(d, J=9.3 Hz, 2H), 7.76 (d, J=9.3 Hz, 2H), 7.70 (d, J=8.0 Hz, 1H), 7.60(d, J=2.1 Hz, 1H), 7.27 (s, 5H), 7.02 (d, J=2.1 Hz, 1H), 5.15 (s, 2H),3.21 (d, J=6.9 Hz, 2H), 2.01-1.87 (m, 1H), 0.97 (d, J=6.6 Hz, 6H).

EXAMPLE 40(29)

Benzyl 2-[2-(4-amidinophenylcarbamoyl)-3-thienyl]-5-(2-methylpropylcarbamoyl)benzoate

TLC:Rf 0.71 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,DMSO-d₆): δ 8.35 (d, J=1.8 Hz, 1H), 8.01 (dd, J=8.0, 1.8 Hz, 1H), 7.70(d, J=9.0 Hz, 2H), 7.67 (d, J=5.0 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.49(d, J=8.0 Hz, 1H), 7.29-7.17 (m, 5H), 7.06 (d, J=5.0 Hz, 1H), 5.12 (s,2H), 3.20 (d, J=6.9 Hz, 2H), 2.00-1.86 (m, 1H), 0.96 (d, J=6.6 Hz, 6H).

EXAMPLE 40(30)

Benzyl2′-(4-amidinophenylcarbamoyl)-4-[(1l-methoxycarbonyl-1-methylethyl)carbamoyl]-2-biphenylcarboxylate

TLC:RF 0.40 (Chloroform:Ethyl acetate:Water=8:2:0.2); NMR (300 MHz,CD₃OD): δ 8.32 (d, J=2.0 Hz, 1H), 7.96 (dd, J=6.9, 2.0 Hz, 2H),7.68-7.66 (m, 3H), 7.62-7.58 (m, 2H), 7.53-7.50 (m, 2H), 7.42 (d, J=7.8Hz, 1H), 7.28-7.25 (m, 3H), 7.17-7.13 (m, 2H), 5.13 (s, 2H), 3.70 (s,3H), 1.55 (s, 6H).

EXAMPLE 40(31)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-(1(S)-carboxy-3-methylbutylcarbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.40 (Chloroform:Ethyl acetate:Water=8:2:0.2); NMR (300 MHz,DMSO-d₆): δ 10.64 (s, 1H), 9.12 (br, 1H), 9.01 (d, J=7.5 Hz, 1H), 8.87(br, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.07 (dd, J=8.1, 2.1 Hz, 1H),7.78-7.59 (m, 4H), 7.59 (m, 1H), 7.55 (m, 1H), 7.44 (d, J=8.1 Hz, 1H),7.35-7.23 (m, 6H), 7.07-7.03 (m, 2H), 5.14 (s, 2H), 5.05 (s, 2H), 4.54(m, 1H), 1.84-1.50 (m, 3H), 0.92 (d, J=6.3 Hz, 3H), 0.87 (d, J=6.0 Hz,3H).

EXAMPLE 40(32)

Benzyl 2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.80 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.98 (br.s, 1H), 9.11 (br.s, 3H), 8.71 (dd, J=4.5, 1.5 Hz, 1H), 8.65(t, J=6.3 Hz, 1H), 8.42 (d, J=1.5 Hz, 1H), 8.11 (dd, J=8.0, 1.5 Hz, 1H),7.93 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.85-7.75 (m, 1H), 7.68(dd, J=8.0, 4.5 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.25-7.15 (m, 3H),7.15-7.05 (m, 2H), 5.03 (s, 2H), 3.14 (d, J=6.3 Hz, 2H), 0.91 (s, 9H).

EXAMPLE 40(33)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.72 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,DMSO-d₆): δ 8.50 (d, J=2.0 Hz, 1H), 8.01 (dd, J=8.0, 2.0 Hz, 1H), 7.83(d, J=9.3 Hz, 2H), 7.77 (d, J=9.3 Hz, 2H), 7.55 (d, J=8.3 Hz, 1H), 7.32(d, J=8.0 Hz, 1H), 7.26-7.16 (m, 3H), 7.10-7.05 (m, 2H), 6.98 (d, J=8.3Hz, 1H), 5.07 (brd, J=12 Hz, 1H), 4.98 (brd, J=12 Hz, 1H), 4.06 (s, 3H),3.25 (s, 2H), 0.99 (s, 9H).

EXAMPLE 40(34)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethyl-1(S)-cyclopentylcarbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.5 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.28 (d, J=1.8 Hz, 1H), 7.95 (dd, J=7.8, 1.8 Hz, 1H),7.70-7.58 (m, 5H), 7.53 (td, J=6.0, 1.8 Hz, 1H), 7.50 (td, J=6.0, 1.8Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.30-7.22 (m, 4H), 7.18-7.12 (m, 2H),5.12 (s, 2H), 4.17 (q, J=7.8 Hz, 1H), 2.08-1.98 (m, 1H), 1.80-1.52 (m,5H), 1.05 (s, 3H), 0.93 (s, 3H).

EXAMPLE 40(35)

Benzyl 2-3-(4-amidinophenylcarbamoyl)-2-thienyl-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.51 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,d₆-DMSO): δ 10.38 (s, 1H), 9.3-8.9 (br, 3H), 8.65 (br.t, J=6.3 Hz, 1H),8.29 (d, J=1.8 Hz, 1H), 8.06 (dd, J=8.1, 1.8 Hz, 1H), 7.83 (d, J=9.0 Hz,2H), 7.77 (d, J=9.0 Hz, 2H), 7.73 (d, J=5.4 Hz, 1H), 7.68 (d, J=5.4 Hz,1H), 7.54 (d, J=8.1 Hz, 1H), 7.3-7.2 (m, 3H), 7.2-7.1 (m, 2H), 5.06 (s,2H), 3.12 (d, J=6.3 Hz, 2H), 0.90 (s, 9H).

EXAMPLE 40(36)

Benzyl 2-[2-(4-amidinophenylcarbamoyl)-3-thienyl]-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.44 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (200 MHz,d₆-DMSO): δ 10.29 (s, 1H), 9.07 (br.s, 3H), 8.59 (br.t, J=6.2 Hz, 1H),8.28 (d, J=1.8 Hz, 1H), 8.06 (dd, J=8.0, 1.8 Hz, 1H), 7.85 (d, J=5.2 Hz,1H), 7.77 (d, J=9.6 Hz, 2H), 7.71 (d, J=9.6 Hz, 2H), 7.47 (d, J=8.0 Hz,1H), 7.3-7.2 (m, 3H), 7.2-7.1 (m, 2H), 7.15 (d, J=5.2 Hz, 1H), 5.08 (s,2H), 3.11 (d, J=6.2 Hz, 2H), 0.89 (s, 9H).

EXAMPLE 40(37)

Benzyl 2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.60 (Chloroform:Ethyl acetate:Water=7:3:0.3); NMR (200 MHz,DMSO-d₆): δ 10.94 (brs, 1H), 9.24 (br, 2H), 9.02 (br, 2H), 8.76 (d,J=4.4 Hz, 1H), 8.16-8.57 (m, 2H), 8.35 (s, 1H), 8.10 (d, J=7.4 Hz, 1H),7.77 (s, 3H), 7.69 (d, J=4.4 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.28 (m;3H), 7.13 (m, 2H), 5.07 (s, 2H), 4.11 (d, J=5.0 Hz, 1H, 3.17 (d, J=4.8Hz, 2H), 0.90 (s, 9H).

EXAMPLE 40(38)

Benzyl2-[2-(4-benzyloxycarbonylamidinophenylcarbamoyl)-5-methyl-3-thienyl]-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.62 (Chloroform:Methanol=10:1); NMR (300 MHz, CDCl₃): δ10.0-9.20 (br, 1H), 8.35 (d, J=1.8 Hz, 1H), 7.95 (dd, J=8.0, 1.8 Hz,1H), 7.71 (d, J=9.0 Hz, 2H), 7.60 (s, 1H), 7.45-7.40 (m, 3H), 7.40-7.25(m, 7H), 7.25-7.15 (m, 3H), 6.53 (s, 1H), 6.60-6.00 (br, 1H), 6.28(br.t, J=6.0 Hz, 1H), 5.20 (s, 2H), 5.18 (s, 2H), 3.30 (d, J=6.0 Hz,2H), 2.47 (s, 3H), 0.99 (s, 9H).

EXAMPLE 40(39)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4′-nitro-4-(2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.40 (Chloroform:Methanol:Water=8:2:0.2); NMR (300 MHz, CD₃OD): δ8.45 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.23 (dd, J=8.0,2.0 Hz,1H), 8.02 (dd, J=8.0,2.0 Hz, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.68 (d, J=9.0Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.23-7.19 (m,3H), 7.14-7.11 (m, 2H), 5.10 (d, J=12.0 Hz, 1H), 5.05 (d, J=12.0 Hz,1H), 3.22 (s, 2H), 0.97 (s, 9H).

EXAMPLE 40(40)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-5-methyl-3-furyl]-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.61 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (200 MHz,d₆-DMSO): δ 13.38 (br.s, 1H), 9.09 (br.s, 3H), 8.60 (t, J=6.2 Hz, 1H),8.34 (d, J=1.6 Hz, 1H), 8.03 (dd, J=8.0, 1.6 Hz, 1H), 7.92 (d, J=8.8 Hz,2H), 7.78 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.4-7.2 (m, 5H),6.42 (s, 1H), 5.11 (s, 2H), 3.13 (d, J=6.2 Hz, 2H), 2.42 (s, 3H), 0.91(s, 9H).

EXAMPLE 40(41)

Benzyl2-[4-(4-amidinophenylcarbamoyl)-2-methyl-pyrimidin-5-yl]-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.71 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.64 (s, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.08 (dd, J=8.0,2.0 Hz,1H), 7.89 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.40 (d, J=8.0 Hz,1H), 7.28-7.19 (m, 3H), 7.16-7.10 (m, 2H), 5.08 (brd, J=12 Hz, 1H), 5.02(brd, J=12 Hz, 1H), 3.25 (s, 2H), 2.80 (s, 3H), 0.99 (s, 9H).

EXAMPLE 40(42)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(1(S)-morpholinocarbonyl-3-methylbutylcarbamoyl)benzoate

TLC:Rf 0.53 (Chloroform:Methanol:Acetic acid=10:1:0.2); NMR (200 MHz,CD₃OD): δ 8.54 (d, J=1.8 Hz, 1H), 8.07 (dd, J=8.2, 1.8 Hz, 1H), 7.85 (d,J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.56 (d, J=8.2 Hz, 1H), 7.43 (d,J=8.2 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.25-7.15 (m, 3H), 7.20-7.10 (m,2H), 5.13 (dd, J=12.0, 4.8 Hz, 1H), 5.01 (like d, 2H), 3.9-3.6 (m, 6H),3.60-3.40 (m, 2H), 2.64 (s, 3H), 1.90-1.70 (m, 2H), 1.70-1.50 (m, 1H),1.01 (d, J=6.2 Hz, 3H), 1.00 (d, J=6.2 Hz, 3H).

EXAMPLE 40(43)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(1(S)-methoxymethyl-2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.50 (Chloroform:Methanol:Water=8:2:0.1); NMR (200 MHz, CD₃OD): δ8.50 (d, J=1.8 Hz, 1H), 8.03 (dd, J=8.2, 1.8 Hz, 1H), 7.85 (d, J=8.6 Hz,2H), 7.76 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz,1H), 7.33 (d, J=8.0 Hz, 1H), 7.26-7.16 (m, 3H), 7.09-7.04 (m, 2H), 5.01(d, J=3.2 Hz, 2H), 4.20 (dd, J=9.2, 4.0 Hz, 1H), 3.72-3.50 (m, 2H), 3.34(s, 3H), 2.64 (s, 3H), 1.02 (s, 9H).

EXAMPLE 40(44)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(1(S)-methoxymethyl-2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.45 (Chloroform:Methanol:Water=8:2:0.1); NMR (200 MHz, CD₃OD): δ8.49 (d, J=2.2 Hz, 1H), 8.01 (dd, J=8.0, 2.2 Hz, 1H), 7.84 (d, J=9.6 Hz,2H), 7.76 (d, J=9.6 Hz, 2H), 7.56 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.2 Hz,1H), 7.26-7.14 (m, 3H), 7.11-7.06 (m, 2H), 6.99 (d, J=8.6 Hz, 1H), 5.03(d, J=8.8 Hz, 2H), 4.21 (dd, J=8.8, 3.6 Hz, 1H), 3.68 (dd, J=10.4, 4.2Hz, 1H), 3.61-3.51 (m, 1H), 3.34 (s, 3H), 1.02 (s, 9H).

EXAMPLE 40(45)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.38 (Chloroform:Methanol:Water=9:1:0.1); NMR (200 MHz, CD₃OD): δ8.72 (d, J=2.0 Hz, 1H), 8.23 (dd, J=8.2, 2.0 Hz, 1H), 7.87 (dt, J=9.2,2.0 Hz, 2H), 7.78 (dt, J=9.2,2.0H, 2H), 7.56 (d, J=8.2, 2.0 Hz, 1H),7.44 (d, J=8.2 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.26-7.16 (m, 3H),7.10-7.06 (m, 2H), 4.98 (d, J=11.2 Hz, 1H), 4.94 (d, J=11.2 Hz, 1H),4.08 (s, 2H), 2.66 (s, 3H), 1.07 (s, 9H).

EXAMPLE 40(46)

Benzyl2-[2-(4-amidino-3-fluorophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.37 (Chloroform:Methanol:Water=8:2:0.1); NMR (300 MHz, d₆-DMSO):δ 9.22 (br s, 3H), 8.63 (t, J=6.3 Hz, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.09(dd, J=7.8, 1.8 Hz, 1H), 7.82 (dd, J=13.5, 1.8 Hz, 1H), 7.72-7.60 (m,3H), 7.52 (d, J=8.1 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.28-7.20 (m, 3H),7.12-7.08 (m, 2H), 5.03 (s, 2H), 3.13 (d, J=6.3 Hz, 2H), 2.64 (s, 3H),0.91 (s, 9H).

EXAMPLE 40(47)

Dibenzyl 4-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]isophthalate

TLC:Rf 0.50 (Chloroform:Methanol:Water=10:2:0.5); NMR (200 MHz, CD₃OD):δ 8.67 (d, J=1.8 Hz, 1H), 8.18 (dd, J=7.6, 1.8 Hz, 1H), 7.83-7.72 (m,4H), 7.50-7.29 (m, 9H), 7.20-7.17 (m, 2H), 7.04-6.98 (m, 2H), 5.38 (s,2H), 4.97 (d, J=4.0 Hz, 2H), 2.62 (s, 3H).

EXAMPLE 40(48)

Benzyl2′-(4-amidinophenylcarbamoyl)-5′-benzyloxycarbonylamino-4-(2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylate

TLC:RF 0.29 (Chloroform:Methanol:Water=8:2:0.2); NMR (200 MHz, CD₃OD): δ8.32 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.0,2.0 Hz, 1H), 7.70-7.58 (m, 6H),7.46-7.35 (m, 6H), 7.23-7.10 (m, 6H), 5.21 (s, 2H), 5.13 (s, 2H), 3.21(s, 2H), 0.96 (s, 9H).

EXAMPLE 40(49)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(1,1,3,3-tetramethylbutylcarbamoyl)benzoate

TLC:Rf 0.64 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.40 (d, J=1.8 Hz, 1H), 7.92 (dd, J=8.0, 1.8 Hz, 1H), 7.84 (d,J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.43 (d,J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.25-7.16 (m, 3H), 7.10-7.04 (m,2H), 5.04 (brd, J=12 Hz, 1H), 4.97 (brd, J=12 Hz, 1H), 2.64 (s, 3H),2.00 (s, 2H), 1.51 (s, 6H), 1.05 (s, 9H).

EXAMPLE 40(50)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-5-methyl-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.29 (Chloroform:Methanol:Water=8:2:0.2) NMR (200 MHz, CD₃OD): δ8.54 (d, J=2.0 Hz, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.05 (dd, J=8.0,2.0 Hz,1H), 7.85 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 7.49 (d, J=2.0 Hz,1H), 7.34 (d, J=8.0 Hz, 1H), 7.24-7.18 (m, 3H), 7.11-7.06 (m, 2H), 5.03(s, 2H), 3.27 (s, 2H), 2.41 (s, 3H), 1.00 (s, 9H).

EXAMPLE 40(51)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[5-(1-methylethyl)-2,2-dimethyldioxan-5-yl]carbamoyl]benzoate

TLC:Rf 0.75 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.47 (d, J=1.8 Hz, 1H), 7.98 (dd, J=7.8, 1.8 Hz, 1H),7.85-7.75 (m, 4H), 7.55 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H),7.23-7.20 (m, 3H), 7.07 (d, J=7.5 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.00(d, J=8.7 Hz, 1H), 5.02 (d, J=13.4 Hz, 2H), 4.23 (d, J=12.0 Hz, 2H),4.07 (d, J=12.0 Hz, 2H), 4.06 (s, 3H), 2.50 (m, 1H), 1.44 (s, 3H), 1.37(s, 3H), 1.02 (d, J=7.2 Hz, 6H).

EXAMPLE 40(52)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[1(S)-(4-ethoxycarbonyloxazol-2-yl)-3-methylbutyl)carbamoyl]benzoate

TLC:Rf 0.86 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.55 (d, J=2.0 Hz, 1H), 8.50 (s, 1H), 8.07 (dd, J=8.0, 2.0 Hz,1H), 7.83 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.4 Hz,1H), 7.33 (d, J=8.0 Hz, 1H), 7.26-7.16 (m, 3H), 7.10-7.05 (m, 2H), 6.99(d, J=8.4 Hz, 1H), 5.45 (dd, J=9.6, 6.3 Hz, 1H), 5.02 (brd, J=12 Hz,1H), 4.97 (brd, J=12 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 4.06 (s, 3H),2.07-1.87 (m, 2H), 1.83-1.68 (m, 1H), 1.35 (t, J=7.2 Hz, 3H), 1.03 (d,J=6.6 Hz, 3H), 1.01 (d, J=6.3 Hz, 3H).

EXAMPLE 40(53)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-N-benzyloxycarbamoyl)-3-methylbutylcarbamoyl]benzoate

TLC:Rf 0.58 (Chloroform:Methanol:Water=8:2:0.2); NMR (300 MHz, DMSO-d₆):δ 10.55 (s, 1H), 9.10 (br, 3H), 8.81 (d, J=7.2 Hz, 1H), 8.45 (dd, J=8.1,1.5 Hz, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.81 (d, J=9.0 Hz, 2H), 7.66 (d,J=8.4 Hz, 1H), 7.39-7.34 (m, 5H), 7.27-7.19 (m, 3H), 7.12-7.06 (m, 3H),5.05 (s, 2H), 4.80 (s, 2H), 4.43 (m, 1H), 4.08 (s, 3H), 1.80-1.60 (m,2H), 1.49 (m, 1H), 0.90 (d, J=6.3 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H).

EXAMPLE 40(54)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)-4-methylbenzoate

TLC:Rf 0.47 (Chloroform:Methanol:Water=8:2:0.2); NMR (200 MHz, CD₃OD): δ8.05 (s, 1H), 7.84 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.52 (d,J=8.4 Hz, 1H), 7.26-7.17 (m, 3H)., 7.12 (s, 1H), 7.09-7.04 (m, 2H), 6.98(d, J=8.4 Hz, 1H), 5.04 (d, J=12.0 Hz, 1H), 4.95 (d, J=12.0 Hz, 1H),4.06 (s, 3H), 3.23 (s, 2H), 2.46 (s, 3H), 1.01 (s, 9H).

EXAMPLE 40(55)

Dibenzyl4-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]isophthalate

TLC:Rf 0.17 (Chloroform:Methanol:Water=9:1:0.1); NMR (200 MHz, CD₃OD): δ8.07 (d, J=1.8 Hz, 1H), 8.23 (dd, J=8.0, 1.8 Hz, 1H), 7.84 (d, J=9.4 Hz,2H), 7.77 (d, J=9.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 1H), 7.50-7.32 (m, 5H),7.26-7.14 (m, 3H), 7.09-7.04 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 5.42 (s,2H), 5.05 (m, 1H), 5.00 (m, 1H), 4.07 (s, 3H).

EXAMPLE 40(56)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(1(S)-hydroxymethyl-3-methylbutylcarbamoyl)-4-methylbenzoate

TLC:Rf 0.58 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.51 (d, J=1.8 Hz, 1H), 8.03 (dd, J=8.0, 1.8 Hz, 1H), 7.83 (d,J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.31 (d,J=8.0 Hz, 1H), 7.25-7.16 (m, 3H), 7.12-7.05 (m, 2H), 6.99 (d, J=8.4 Hz,1H), 5.07 (brd, J=12 Hz, 1H), 4.98 (brd, J=12 Hz, 1H), 4.32-4.22 (m,1H), 4.06 (s, 3H), 3.61 (d, J=5.7 Hz, 2H), 1.80-1.65 (m, 1H), 1.65-1.40(m, 2H), 0.98 (d, J=6.6 Hz, 6H).

EXAMPLE 40(57)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(4,4-dimethyloxolan-3(S)-yl)carbamoyl]-4-methylbenzoate

TLC:Rf 0.70 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.50 (d, J=1.8 Hz, 1H), 8.02 (dd, J=8.0, 1.8 Hz, 1H), 7.83 (d,J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.33 (d,J=8.0 Hz, 1H), 7.24-7.17 (m, 3H), 7.12-7.05 (m, 2H), 6.99 (d, J=8.4 Hz,1H), 5.07 (brd, J=12 Hz, 1H), 4.98 (brd, J=12 Hz, 1H), 4.48 (dd, J=7.5,5.4 Hz, 1H), 4.23 (dd, J=9.3, 7.5 Hz, 1H), 4.06 (s, 3H), 3.77 (dd,J=9.3, 5.4 Hz, 1H), 3.64 (d, J=8.4 Hz, 1H), 3.59 (d, J=8.4 Hz, 1H), 1.21(s, 3H), 1.08 (s, 3H).

EXAMPLE 40(58)

Benzyl 2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(1(R),2,2-trimethylpropylcarbamoyl)benzoate

TLC:Rf 0.65 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.46 (d, J=1.8 Hz, 1H), 7.99 (dd, J=8.0, 1.8 Hz, 1H), 7.83 (d,J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.31 (d,J=8.0 Hz, 1H), 7.25-7.16 (m, 3H), 7.10-7.06 (m, 2H), 6.99 (d, J=8.4 Hz,1H), 5.07 (brd, J=12 Hz, 1H), 4.98 (brd, J=12 Hz, 1H), 4.10 (q, J=7.0Hz, 1H), 4.06 (s, 3H), 1.20 (d, J=7.0 Hz, 3H), 1.00 (s, 9H).

EXAMPLE 40(59)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(R)-2,2-dimethylcyclopentyl)carbamoyl]benzoate

TLC:Rf 0.70 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.48 (d, J=1.8 Hz, 1H), 8.00 (dd, J=8.0, 1.8 Hz, 1H), 7.83 (d,J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.54 (d, J=8.4 Hz, 1H), 7.31 (d,J=8.0 Hz, 1H), 7.26-7.16 (m, 3H), 7.10-7.05 (m, 2H), 6.98 (d, J=8.4 Hz,1H), 5.07 (brd, J=12 Hz, 1H), 4.98 (brd, J=12 Hz, 1H), 4.21 (brt, J=7.0Hz, 1H), 4.06 (s, 3H), 2.15-2.03 (m, 1H), 1.84-1.54 (m, 5H), 1.09 (s,3H), 0.98 (s, 3H).

EXAMPLE 40(60)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-methylaminomethyl-3-methylbutyl)carbamoyl]benzoatedihydrochloride

TLC:Rf 0.38 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.60 (d, J=1.8 Hz, 1H), 8.12 (dd, J=8.2, 1.8 Hz, 1H), 7.78 (d,J=9.1 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.24-7.18(m, 3H), 7.10-7.05 (m, 2H), 7.01 (d, J=8.4 Hz, 1H), 5.04 (d, J=8.2 Hz,1H), 2H), 4.54 (m, 1H), 4.07 (s, 3H), 2.76 (s, 3H), 1.80-1.64 (m, 2H),1.40 (m, 1H), 1.01 (d, J=6.3 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H).

EXAMPLE 40(61)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(4,4-dimethyl-2-oxooxolan-3(S)-yl)carbamoyl]benzoate

TLC:Rf 0.70 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.57 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H), 7.83 (d,J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.56 (d, J=8.4 Hz, 1H), 7.35 (d,J=8.0 Hz, 1H), 7.28-7.17 (m, 3H), 7.10-7.04 (m, 2H), 6.99 (d, J=8.4 Hz,1H), 5.07 (brd, J=12 Hz, 1H), 5.00 (s, 1H), 4.99 (brd, J=12 Hz, 1H),4.19 (d, J=9.0 Hz, 1H), 4.14 (d, J=9.0 Hz, 1H), 1.27 (s, 3H), 1.12 (s,3H).

EXAMPLE 40(62)

Benzyl 2-[2-(4-amidinophenylcarbamoyl) -3-thienyl]-5-[(1(S)-acetyloxymethyl-2,2-dimethylpropyl)carbamoyl]benzoate

TLC:Rf 0.30 (Chloroform:Methanol:Acetic acid=10:1:0.2); NMR (200 MHz,CD₃OD): δ 8.33 (d, J=2.0 Hz, 1H), 7.99 (dd, J=8.0, 2.0 Hz, 1H), 7.71 (d,J=9.2 Hz, 2H), 7.70-7.60 (m, 1H), 7.62 (d, J=9.2 Hz, 2H), 7.49 (d, J=8.0Hz, 1H), 7.30-7.15 (m, 5H), 7.06 (d, J=5.2 Hz, 1H), 5.13 (s, 2H), 4.46(dd, J=10.4, 3.0 Hz, 1H), 4.26 (dd, J=10.4, 3.0 Hz, 1H), 4.13 (t, J=10.4Hz, 1H), 1.95 (s, 3H), 1.03 (s, 9H).

EXAMPLE 40(63)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[4-benyzloxycarbonyl-4-(2-methyl-2-propenyl)piperidinyl]carbonyl]benzoate

TLC:Rf 0.58 (Chloroform:Methanol:Water=8:2:0.1); NMR (300 MHz, CD₃OD): δ8.05 (d, J=2.1 Hz, 1H), 7.83 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H),7.61 (dd, J=8.1, 2.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.44-7.29 (m, 5H),7.31 (d, J=7.8 Hz, 1H), 7.26-7.16 (m, 3H), 7.09-7.05 (m, 2H), 6.99 (d,J=8.7 Hz, 1H), 5.18 (s, 2H), 5.01 (d, J=17.1 Hz, 2H), 4.80 (m, 1H), 4.67(s, 1H), 4.45-4.30 (m, 2H*½, each of rotamers), 4.06 (s, 3H), 3.80-3.70(m, 2H*½, each of rotamers), 3.31-3.20 (m, 2H*½, each of rotamers),3.10-3.00 (m, 2H*½, each of rotamers), 2.40 (m, 2H), 2.40-2.20 (m,2H*1/2, each of rotamers), 2.20-2.10 (m, 2H*½, each of rotamers), 1.62(s, 3H), 1.62-1.50 (m, 2H).

EXAMPLE 40(64)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[1(S)-[N-methyl-N-(1-iminoethyl)aminomethyl]-3-methylbutyl]benzoateacetic acetate

TLC:Rf 0.25 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.52 and 8.49 (s, 1H), 8.04 (m, 1H), 7.84 (d, J=9.0 Hz, 2H),7.79 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.26-7.06 (m, 5H), 7.00(d, J=8.4 Hz, 1H), 5.08 (d, J=12.6 Hz, 1H), 4.97 (d, J=12.6 Hz, 1H),4.50 (m, 1H), 4.07 (s, 3H), 3.64 (d, J=6.9 Hz, 2H), 3.21 (s, 3H), 2.35and 2.32 (s, 3H), 1.99 (s, 3H), 1.90-1.62 (m, 2H), 1.41 (m, 1H), 0.99(m, 6H).

EXAMPLE 40(65)

Benzyl 2′-(4-amidinophenylcarbamoyl)-4′-benzyloxycarbonylamino-4-(1(R),2,2-trimethylpropylcarbamoyl)-2-biphenylearboxylate

TLC:RF 0.46 (Chloroform:Methanol:Water=8:2:0.2); NMR (200 MHz, CDCl₃): δ8.25 (d, J=2.0 Hz, 1H), 8.15 (br.d, J=9.6 Hz, 1H), 7.90 (dd, J=8.0, 2.0Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.67 (d, J=9.0 Hz, 2H), 7.60 (d, J=9.0Hz, 2H), 7.51-7.31 (m, 7H), 7.22-7.08 (m, 6H), 5.23 (s, 2H), 5.10 (s,2H), 4.05 (m, 1H), 1.15 (d, J=7.0 Hz, 3H), 0.94 (s, 9H).

EXAMPLE 40(66)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[1-(2,2-dimethylpropyl)tetrazol-5-yl]benzoate

TLC:Rf 0.48 (Chloroform:Methanol:Acetic acid=10:1:0.2); NMR (300 MHz,CD₃OD): δ 8.38 (d, J=2.0 Hz, 1H), 7.95 (dd, J=8.0, 2.0 Hz, 1H), 7.85 (d,J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.48 (d,J=8.0 Hz, 1H), 7.3-7.1 (m, 3H), 7.15-7.05 (m, 2H), 7.01 (d, J=8.4 Hz,1H), 5.09 (d, J=11.7 Hz, 1H), 4.99 (d, J=11.7 Hz, 1H), 4.44 (s, 2H),4.07 (s, 3H), 0.90 (s, 9H).

EXAMPLE 40(67)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[1-(1-iminoethyl)-4-(2-methylpropyl)piperidin-4-yl]carbamoyl]benzoate

TLC:Rf 0.87 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (300 MHz,CD₃OD): δ 8.46 (d, J=1.8 Hz, 1H), 8.01 (dd, J=8.1, 1.8 Hz, 1H), 7.83 (d,J=9.3 Hz, 2H), 7.78 (d, J=9.3 Hz, 2H), 7.53 (d, J=8.7 Hz, 1H), 7.33 (d,J=8.1 Hz, 1H), 7.25-7.17 (m, 3H), 7.08-7.05 (m, 2H), 6.99 (d, J=8.7 Hz,1H), 5.02 (d, J=18.6 Hz, 2H), 4.06 (s, 3H), 3.96-3.84 (m, 2H), 3.59-3.37(m, 2H), 2.73-2.62 (m, 2H), 2.34 (s, 3H), 1.86-1.73 (m, 5H), 0.98 (d,J=6.0 Hz, 6H).

EXAMPLE 40(68)

Benzyl 3-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-6-[(1(R),2,2-trimethylpropyl)carbamoyl]-2-pyridinecarboxylate

TLC:Rf 0.30 (Chloroform:Methanol:Water=8:2:0.2); NMR (200 MHz, CD₃OD): δ8.29 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.85 (d, J=9.0 Hz, 2H),7.77 (d, J=9.0 Hz, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.28-7.17 (m, 3H),7.09-7.04 (m, 2H), 7.02 (d, J=8.4 Hz, 1H), 5.20-4.94 (m, 2H), 4.07 (s,3H), 4.06 (m, 1H), 1.24 (d, J=7.0 Hz, 3H), 1.00 (s, 9H).

EXAMPLE 40(69)

Benzyl 2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(t-butylcarbamoyl)benzoate

TLC:Rf 0.40 (Chloroform:Methanol:Acetic acid=10:1:0.5); NMR (200 MHz,CD₃OD): δ 8.41 (d, J=1.8 Hz, 1H), 7.93 (dd, J=8.4, 1.8 Hz, 1H), 7.83 (d,J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.27 (d,J=8.4 Hz, 1H), 7.20-7.04 (m, 5H), 6.97 (d, J=8.4 Hz, 1H), 5.01 (d, J=8.2Hz, 2H), 4.06 (s, 3H), 1.48 (s, 9H).

EXAMPLE 40(70)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2,2-trichloroethylcarbamoyl)benzoate

TLC:Rf 0.25 (Chloroform:Methanol:Acetic acid=10:1:0.5); NMR (300 MHz,CD₃OD): δ 8.57 (d, J=1.8 Hz, 1H), 8.08 (dd, J=7.8, 1.8 Hz, 1H), 7.83 (d,J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.56 (d, J=8.4 Hz, 1H), 7.36 (d,J=7.8 Hz, 1H), 7.25-7.07 (m, 6H), 7.00 (d, J=8.4 Hz, 1H), 5.03 (d,J=17.7 Hz, 2H), 4.49 (s, 2H), 4.07 (s, 3H).

EXAMPLE 40 (71)

Benzyl2-[3-(4-amidinophenylcarbamoyl)-2-thienyl]-6-(t-butylcarbamoyl)-2-pyridinecarboxylate

TLC:Rf 0.30 (Chloroform:Methanol:Water=8:2:0.2); NMR (300 MHz, CD₃OD): δ8.23 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.79 (d, J=9.0 Hz, 2H),7.74 (d, J=9.0 Hz, 2H), 7.59 (d, J=5.4 Hz, 1H), 7.52 (d, J=5.4 Hz, 1H),7.25-7.21 (m, 3H), 7.16-7.13 (m, 2H), 5 13 (s, 2H), 1.48 (s, 9H).

EXAMPLE 40(72)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2,2-trifluoroethylcarbamoyl)benzoate

TLC:Rf 0.41 (Chloroform:Methanol:Water=8:2:0.2); NMR (300 MHz, CD₃OD): δ8.56 (d, J=1.8 Hz, 1H), 8.06 (dd, J=8.1, 1.8 Hz, 1H), 7.83 (d, J=9.0 Hz,2H), 7.78 (d, J=9.0 Hz, 2H), 7.54 (d, J=8.7 Hz, 1H), 7.35 (d, J=8.1 Hz,1H), 7.25-7.17 (m, 3H), 7.07 (d, J=8.7 Hz, 1H), 6.99 (d, J=J=8.7 Hz,1H), 5.07 (d, J=11.7 Hz, 1H), 4.99 (d, J=11.7 Hz, 1H), 4.13 (q, J=9.3Hz, 2H), 4.07 (s, 3H).

EXAMPLE 40(73)

Benzyl2-[2-[(2-amidinopyrimidin-5-yl)carbamoyl]-6-methoxy-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoate

TLC:Rf 0.57 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,d₆-DMSO): δ 11.05-10.85 (br, 1H), 9.45 (br.s, 3H), 9.30 (s, 2H), 8.61(t, J=6.6 Hz, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.09 (dd, J=7.8, 1.8 Hz, 1H),7.69 (d, J=8.7 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.30-7.15 (m, 3H),7.20-7.05 (m, 3H), 5.05 (s, 2H), 4.09 (s, 3H), 3.13 (d, J=6.6 Hz, 2H),0.97 (s, 9H).

EXAMPLE 40(74)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[1(S)-(2-benzyloxycarbonylaminoethyl)-3-methylbutyl]carbamoyl]benzoate

TLC:Rf 0.32 (Chloroform:Methanol:Water=8:2:0.2); NMR (300 MHz, CD₃OD): δ8.51 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.0,2.0 Hz, 1H), 7.83 (d, J=9.0 Hz,2H), 7.76 (d, J=9.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.33-7.16 (m, 9H),7.09-7.06 (m, 2H), 6.99 (d, J=8.0 Hz, 1H), 5.15-5.00 (m, 4H), 4.27 (m,1H), 4.06 (s, 3H), 3.34-3.07 (m, 2H), 1.85-1.30 (m, 5H), 0.95 (d, J=6.3Hz, 6H).

EXAMPLE 40(75)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2,2-diethylbutyloxy)carbamoyl]benzoate

TLC:Rf 0.54 (Chloroform:Methanol:Water=8:2:0.2); NMR (200 MHz, CD₃OD):δ8.68 (d, J=1.8 Hz, 1H), 8.19 (d, J=8.0, 1.8 Hz, 1H), 7.85 (d, J=8.8 Hz,2H), 7.77 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.6 Hz, 1H), 7.36 (d, J=8.0 Hz,1H), 7.28-7.18 (m, 3H), 7.13-7.08 (m, 2H), 6.99 (d, J=8.6 Hz, 1H), 5.09(d, J=12.0 Hz, 1H), 4.97 (d, J=12.0 Hz, 1H), 4.16 (s, 2H), 4.08 (s, 3H),1.43 (q, J=7.6 Hz, 6H), 0.88 (t, J=7.6 Hz, 9H).

EXAMPLE 40(76)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2,2-dimethyl-3-hydroxypropyl)carbamoyl]benzoate

TLC:Rf 0.29 (Chloroform:Methanol:Water=8:2:0.1); NMR (200 MHz, CD₃OD): δ8.51 (d, J=2.0 Hz, 1H), 8.03 (dd, J=8.0, 2.0 Hz, 1H), 7.84 (d, J=9.2 Hz,2H), 7.76 (d, J=9.2 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.0 Hz,1H), 7.23-7.17 (m, 3H), 7.10-7.05 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 5.03(d, J=8.8 Hz, 2H), 4.06 (s, 3H), 3.34-3.28 (m, 4H), 0.96 (s, 6H).

EXAMPLE 40(77)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2,2-diethylbutyl)carbamoyl]benzoate

TLC:Rf 0.56 (Chloroform:Methanol:Water=8:2:0.2); NMR (300 MHz, CD₃OD): δ8.45 (d, J=1.8 Hz, 1H), 7.97 (dd, J=8.1, 1.8 Hz, 1H), 7.83 (d, J=9.0 Hz,2H), 7.78 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.1 Hz,1H), 7.25-7.17 (m, 3H), 7.09-7.07 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 5.07(d, J=11.4 Hz, 1H), 4.97 (d, J=11.4 Hz, 1H), 4.06 (s, 3H), 3.35 (s, 2H),1.33 (q, J=7.5 Hz, 6H), 0.88 (t, J=7.5 Hz, 9H).

EXAMPLE 40(78)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[((1-hydroxymethyl)cyclobutylmethyl)carbamoyl]benzoate

TLC:Rf 0.30 (Chloroform:Methanol:Water=8:2:0.1); NMR (300 MHz, CD₃OD): δ8.50 (d, J=1.8 Hz, 1H), 8.01 (dd, J=7.8, 1.8 Hz, 1H), 7.83 (d, J=9.0 Hz,2H), 7.77 (d, J=9.0 Hz, 2H), 7.54 (dd, J=8.4, 1.8 Hz, 1H), 7.32 (d,J=7.8 Hz, 1H), 7.24-7.17 (m, 3H), 7.08-7.06 (m, 2H), 6.99 (dd, J=8.4,1.8 Hz, 1H), 5.02 (br d, J=16.5 Hz, 2H), 4.06 (s, 3H), 3.57 (s, 2H),3.56 (s, 2H), 1.93-1.82 (m, 6H).

EXAMPLE 40(79)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-ethyl-2-hydroxymethylbutyl)carbamoyl]benzoate

TLC:Rf 0.31 (Chloroform:Methanol:Water=8:2:0.1); NMR (300 MHz, CD₃OD): δ8.50 (d, J=1.8 Hz, 1H), 8.01 (dd, J=8.1, 1.8 Hz, 1H), 7.83 (d, J=9.0 Hz,2H), 7.77 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.1 Hz,1H), 7.24-7.17 (m, 3H), 7.08-7.06 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 5.02(br d, J=17.4 Hz, 2H), 4.06 (s, 3H), 3.36 (s, 2H), 3.35 (s, 2H), 1.35(septet, J=7.5 Hz, 4H), 0.90 (t, J=7.5 Hz, 6H).

EXAMPLE 40(80)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[((1-hydroxymethyl)cyclopentylmethyl)carbamoyl]benzoate

TLC:Rf 0.28 (Chloroform:Methanol:Water=8:2:0.1); NMR (300 MHz, CD₃OD): δ8.50 (d, J=1.8 Hz, 1H), 8.02 (dd, J=8.1, 1.8 Hz, 1H), 7.83 (d, J=9.3 Hz,2H), 7.77 (d, J=9.3 Hz, 2H), 7.54 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.1 Hz,1H), 7.25-7.16 (m, 3H), 7.09-7.06 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 5.02(d, J=16.8 Hz, 2H), 4.06 (s, 3H), 3.44 (s, 2H), 3.39 (s, 2H), 1.80-1.60(m, 4H), 1.60-1.40 (m, 2H).

EXAMPLE 40(81)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-propyl-2-hydroxymethylpentyl)carbamoyl]benzoate

TLC:Rf 0.60 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.49 (d, J=1.8 Hz, 1H), 8.00 (dd, J=8.1, 1.8 Hz, 1H),7.85-7.75 (m, 4H), 7.55 (d, J=8.7 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H),7.23-7.20 (m, 3H), 7.09-7.06 (m, 2H), 6.99 (d, J=8.7 Hz, 1H), 5.02 (d,J=17.4 Hz, 2H), 4.06 (s, 3H), 3.60 (m, 1H), 3.39-3.25 (m, 3H), 1.40-1.20(m, 8H), 0.93 (t, J=6.9 Hz, 6H).

EXAMPLE 40(82)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-(2-methylpropyl)-2-hydroxymethyl-4-methylpentyl)carbamoyl]benzoate

TLC:Rf 0.38 (Chloroform:Methanol:Water=8:2:0.2); NMR (300 MHz, CD₃OD): δ8.49 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.1, 2.1 Hz, 1H), 7.83 (d, J=9.0 Hz,2H), 7.77 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.7 Hz, 1H), 7.34 (d, J=8.1 Hz,1H), 7.24-7.20 (m, 3H), 7.09-7.06 (m, 2H), 6.99 (d, J=8.7 Hz, 1H), 1H),5.15-4.95 (m, 2H), 4.07 (s, 3H), 3.49 (s, 2H), 3.45 (s, 2H), 1.86-1.76(2H), 1.50-1.30 (m, 4H), 0.98 (d, J=6.6 Hz, 12H).

EXAMPLE 40(83)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1-hydroxymethylcyclopentyl)carbamoyl]benzoate

TLC:Rf 0.38 (Chloroform:Methanol:Water=8 8:2:0.2); NMR (300 MHz, CD₃OD):δ 8.45 (d, J=2.1 Hz, 1H), 7.98 (dd, J=7.8, 2.1 Hz, 1H), 7.83 (d, J=9.0Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.29 (d, J=7.8Hz, 1H), 7.25-7.17 (m, 3H), 7.09-7.06 (m, 2H), 6.98 (d, J=8.4 Hz, 1H),5.15-4.90 (m, 2H), 4.60 (s, 3H), 3.80 (s, 2H), 2.18-2.01 (m, 2H),1.96-1.70 (m, 4H), 1.70-1.52 (m, 2H).

EXAMPLE 40(84)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl)-5-[(1-(2-methylpropyl)-1-hydroxymethyl-3-methylbutyl)carbamoyl]benzoate

TLC:Rf 0.38 (Chloroform:Methanol:Water=8:2:0.2); NMR (300 MHz, CD₃OD): δ8.42 (d, J=2.1 Hz, 1H), 7.93 (dd, J=7.8, 2.1 Hz, 1H), 7.83 (d, J=9.0 Hz,2H), 7.78 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.30 (d, J=7.8 Hz,1H), 7.23-7.18 (m, 3H), 7.09-7.06 (m, 2H), 6.98 (d, J=8.4 Hz, 1H),5.15-4.90 (m, 2H), 4.06 (s, 3H), 3.80 (s, 2H), 1.92-1.76 (m, 6H), 0.99(d, J=6.0 Hz, 6H), 0.98 (d, J=6.3 Hz, 6H).

EXAMPLE 40(85)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-(hydroxymethyl)-2(S)-methylbutyl)carbamoyl]benzoate.

TLC:Rf 0.20, (Chloroform:Methanol:Acetic acid=10:1:0.5); NMR (300 MHz,CD₃OD): δ 8.52 (d, J=1.8 Hz, 1H), 8.04 (dd, J=7.8, 1.8 Hz, 1H), 7.83 (d,J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.32 (d,J=7.8 Hz, 1H), 7.30-7.03 (m, 5H), 6.98 (d, J=8.4 Hz, 1H), 5.03 (d,J=15.6 Hz, 2H), 4.06 (s, 3H), 4.03 (m, 1H), 3.78 (m, 2H), 1.80 (m, 1H),1.60 (m, 1H), 1.23 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.95 (t, J=7.5 Hz,3H).

EXAMPLE 40(86)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-isopropyl-3-benzyloxycarbonylaminopropyl)carbamoyl]benzoate

TLC:Rf 0.40 (Chloroform:Methanol:Acetic acid=10:1:0.5); NMR (200 MHz,CD₃OD): δ 8.51 (d, J=1.8 Hz, 1H), 8.05 (m, 1H), 7.81-7.77 (m, 4H), 7.50(d, J=8.4 Hz, 1H), 7.39-7.02 (m, 11H), 6.93 (d, J=8.4 Hz, 1H), 5.02 (m,4H), 4.46 (dd, J=14.0,7.4 Hz, 2H), 3.95 (m, 1H), 3.69 (m, 1H), 3.10 (m,1H), 1.83 (m, 2H), 1.70 (m, 1H), 1.48 (t, J=7.0 Hz, 3H), 0.97 (d, J=7.0Hz, 6H).

EXAMPLE 40(87)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-(2-benzyloxycarbonylaminoethyl)-3-methylbutyl)carbamoyl]benzoate

TLC:Rf 0.27 (Chloroform:Methanol:Acetic acid=20:2:1); NMR (300 MHz,CD₃OD): δ 8.51 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.0, 2.0 Hz, 1H), 7.81 (d,J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.36-7.16(m, 9H), 7.10-7.05 (m, 2H), 6.96 (d, J=8.4 Hz, 1H), 5.07 (brd, J=12 Hz,1H), 5.05 (s, 2H), 4.98 (brd, J=12 Hz, 1H), 4.52-4.42 (m, 2H), 4.33-4.20(m, 1H), 3.36-3.25 (m, 1H), 3.20-3.05 (m, 1H), 1.90-1.50 (m, 4H), 1.48(t, J=7.2 Hz, 3H), 1.42-1.30 (m, 1H), 0.95 (d, J=6.0 Hz, 6H).

EXAMPLE 40(88)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-(2-benzyloxycarbonylaminoethyl)-2(S)-methylbutyl)carbamoyl]benzoate

TLC:Rf 0.30 (Chloroform:Methanol:Acetic acid=20:2:1); NMR (300 MHz,CD₃OD): δ 8.51 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.0, 2.0 Hz, 1H), 7.82 (d,J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.36-7.16(m, 9H), 7.12-7.05 (m, 2H), 6.97 (d, J=8.4 Hz, 1H), 5.07 (brd, J=12 Hz,1H), 5.04 (s, 2H), 4.97 (brd, J=12 Hz, 1H), 4.52-4.42 (m, 2H), 4.12-3.98(m, 1H), 3.33-3.20 (m, 1H), 3.15-3.00 (m, 1H), 1.95-1.80 (m, 1H),1.75-1.45 (m, 3H), 1.49 (t, J=7.2 Hz, 3H), 1.30-1.18 (m, 1H), 0.97 (d,J=6.6 Hz, 3H), 0.94 (t, J=7.5 Hz, 3H).

EXAMPLE 41(1)-41(90)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 2, with the proviso that some compounds were notconverted to salt thereof, or were converted to different salt thereof;using the compound prepared in Reference Example 40(1)-40(88).

EXAMPLE 41(1)

2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1,2,2-trimethylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.35 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 11.05(1H, s), 9.23 (2H, brs), 9.00 (2H, brs), 8.89 (1H, brd, J=5.5 Hz), 8.70(1H, s), 8.38 (1H, d, J=2.0 Hz), 8.25 (1H, d, J=9.0 Hz), 8.03 (1H, dd,J=8.0 Hz, 2.0 Hz), 7.92 (1H, d, J=5.5 Hz), 7.78 (2H, d, J=9.0 Hz), 7.74(2H, d, J=9.0 Hz), 7.45 (1H, d, J=8.0 Hz), 3.99 (1H, dq, J=9.0 Hz, 7.0Hz), 2.36 (3H, s), 1.08 (3H, d, J=7.0 Hz), 0.89 (9H, s).

EXAMPLE 41(2)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(2-methylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.13 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.85 (1H, s), 9.21 (2H, brs), 8.96 (2H, brs), 8.71 (1H, brt, J=5.5 Hz),8.42 (1H, d, J=2.0 Hz), 8.03 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.92 (2H, d,J=8.5 Hz), 7.78 (2H, d, J=8.5 Hz), 7.64 (1H, d, J=8.0 Hz), 7.55 (1H, d,J=8.0 Hz), 7.30 (1H, d, J=8.0 Hz), 3.11 (2H, brt, J=6.5 Hz), 2.67 (3H,s), 2.37 (3H, s), 1.94-1.80 (1H, m), 0.90 (6H, d, J=6.5 Hz).

EXAMPLE 41(3)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1,2,2-trimethylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.16 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.86 (1H, s), 9.22 (2H, brs), 8.98 (2H, brs), 8.38 (1H, d, J=1.5 Hz),8.23 (1H, brd, J=9.0 Hz), 8.02 (1H, dd, J=8.0 Hz, 1.5 Hz), 7.93 (2H, d,J=8.5 Hz), 7.79 (2H, d, J=8.5 Hz), 7.62 (1H, d, J=8.0 Hz), 7.56 (1H, d,J=8.0 Hz), 7.29 (1H, d, J=8.0 Hz), 4.01 (1H, dq, J=9.0 Hz, 7.0 Hz), 2.67(3H, s), 2.38 (3H, s), 1.10 (3H, d, J=7.0 Hz), 0.92 (9H, s).

EXAMPLE 41(4)

2′-(4-amidinophenylcarbamoyl)-4-(1,1-dimethylpropylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.15 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (1H, s), 9.15 (2H, br s), 8.84 (2H, br s), 8.20 (1H, d, J=2.1 Hz),7.90 (1H, dd, J=2.1, 7.8 Hz), 7.81 (1H, s), 7.72 (4H, s), 7.72-7.67 (1H,m), 7.59-7.49 (2H, m), 7.28 (1H, d, J=8.1 Hz), 7.26-7.23 (1H, m), 2.33(3H, s), 1.77 (2H, q, J=7.5 Hz), 1.31 (6H, s), 0.79 (3H, t, J=7.5 Hz).

EXAMPLE 41(5)

2′-(4-amidinophenylcarbamoyl)-4-[(1(S)-t-butyl-2-methoxycarbonylethyl)carbamoyl]-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.18 (Chloroform:Methanol:Water=10:2:1); NMR (d₆-DMSO): δ 10.6(1H, s), 9.14 (2H, br s), 8.80 (2H, br s), 8.29 (1H, d, J=9.3 Hz), 8.23(1H, s), 7.90 (1H, d, J=8.8 Hz), 7.73-7.68 (5H, m), 7.60-7.48 (2H, m),7.32-7.25 (2H, m), 4.28 (1H, t, J=8.8 Hz), 3.51 (3H, s), 2.72-2.40 (2H,m), 2.30 (3H, s), 0.89 (9H, s).

EXAMPLE 41(6)

2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethylcyclohexylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.36 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.0 (1H, br), 10.56 (1H, s), 9.16 (2H, s), 8.89 (2H, s), 8.25 (1H,d, J=2.0 Hz), 8.10 (1H, d, J=9.0 Hz), 7.94 (1H, dd, J=2.0, 8.0 Hz), 7.73(4H, like s), 7.69 (1H, dd, J=2.0, 8.0 Hz), 7.5-7.45 (2H, m), 7.30 (1H,d, J=8.0 Hz), 7.25 (1H, dd, J=2.0, 8.0 Hz), 3.81 (1H, m), 2.36 (3H, s),1.8-1.6 (1H, m), 1.7-1.3 (4H, m), 1.4-1.2 (3H, m), 0.89 (3H, s), 0.84(3H, s).

EXAMPLE 41(7)

2′-(4-amidinophenylcarbamoyl)-4-(1-isopropyl-2-methylpropylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.31(Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.57 (1H, s), 9.15 (2H, s), 8.81 (2H, s), 8.29 (1H, d, J=2.0 Hz), 8.02(1H, d, J=10.0 Hz), 7.97 (1H, dd, J=2.0,8.0 Hz), 7.74 (4H, s), 7.71 (1H,dd, J=2.0,8.0 Hz), 7.58 (1H, dt, J=2.0,8.0 Hz), 7.54 (1H, dt, J=2.0,8.0Hz), 7.32 (1H, d, J=8.0 Hz), 7.27 (1H, dd, J=2.0,8.0 Hz), 3.67 (1H, dt,J=7.2, 10.0 Hz), 2.33 (3H, s), 1.91 (2H, m), 0.87 (6H, d, J=7.5 Hz),0.85 (6H, d, J=7.5 Hz).

EXAMPLE 41(8)

2′-(4-amidinophenylcarbamoyl)-4-[(4,4-dimethyloxolan-3(S)-yl)carbamoyl]-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.15 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (s, 1H), 9.14 (br s, 2H), 8.78 (br s, 2H), 8.51 (d, J=8.8 Hz, 1H),8.31 (d, J=1.4 Hz, 1H), 7.98 (dd, J=8.0,1.4 Hz, 1H), 7.72-7.68 (m, 5H),7.60-7.50 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.30-7.25 (m, 1H), 7.30-7.25(m, 1H), 4.40-4.25 (m, 1H), 4.12-4.03 (m, 1H), 3.70-3.60 (m, 1H),3.54-3.39 (m, 2H, 2.29 (s, 3H), 1.08 (s, 3H), 0.93 (s, 3H).

EXAMPLE 41(9)

2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(2-methylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.34 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ11.00 (s, 1H), 9.12 (s, 2H), 8.92 (s, 2H), 8.73 (dd, J=4.8, 2.1 Hz, 1H),8.71 (br.d, J=6.3 Hz, 1H), 8.43 (d, J=1.8 Hz, 1H), 8.05 (dd, J=7.8, 1.8Hz, 1H), 7.95 (d, J=9.0 Hz, 2H), 7.8-7.7 (m, 1H), 7.77 (d, J=9.0 Hz,2H), 7.71 (dd, J=7.8, 4.8 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 5.0-4.2 (br,1H), 3.12 (t, J=6.3 Hz, 2H), 2.36 (s, 3H), 1.88 (like septet, J=6.3 Hz,1H), 0.91 (d, J=6.3 Hz, 6H).

EXAMPLE 41(10)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(3-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.25 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.86(s, 1H), 9.22 (brs, 2H), 8.97 (brs, 2H), 8.66 (brt, J=6.5 Hz, 1H), 8.41(d, J=1.8 Hz, 1H), 8.04 (dd, J=8.0, 1.8 Hz, 1H), 7.93 (d, J=8.7 Hz, 2H),7.79 (d, J=8.7 Hz, 2H), 7.64 (d, J=8.0 Hz, 1H), 9.56 (d, J=8.0 Hz, 1H),7.31 (d, J=8.0 Hz, 1H), 3.19 (d, J=6.5 Hz, 2H), 3.15 (s, 2H), 2.67 (s,3H), 2.38 (s, 3H), 0.84 (s, 6H).

EXAMPLE 41(11)

2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1,2,2-trimethylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.36 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ11.00 (s, 1H), 9.20 (br.s, 2H), 8.93 (br.s, 2H), 8.73 (dd, J=4.8, 2.1Hz, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.25 (d, J=9.6 Hz, 1H), 8.04 (dd,J=7.8, 1.8 Hz, 1H), 7.95 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H),7.75-7.65 (m, 2H), 7.33 (d, J=7.8 Hz, 1H), 6.5-5.0 (br, 1H), 4.01 (m,1H), 2.36 (s, 3H), 1.11 (d, J=6.6 Hz, 3H), 0.92 (s, 9H).

EXAMPLE 41(12)

2′-(4-amidinophenylcarbamoyl)-4-[(1(R),2,2-trimethylpropyl)carbamoyl]-2-biphenylcarboxylic acidmethanesulfonate

TLC:Rf 0.14 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.15 (br s, 2H), 8.85 (br s, 2H), 8.26 (d, J=1.8 Hz, 1H),8.18 (d, J=8.6 Hz, 1H), 7.95 (dd, J=8.0, 1.8 Hz, 1H), 7.73-7.58 (m, 5H),7.60-7.48 (m, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.28-7.24 (m, 1H), 4.05-3.90(m, 1H), 2.33 (s, 3H), 1.07 (d, J=6.8 Hz, 3H), 0.89 (s, 9H).

EXAMPLE 41(13)

2′-(4-amidinophenylcarbamoyl)-4-[(1(S),2,2-trimethylpropyl)carbamoyl]-2-biphenylcarboxylic acidmethanesulfonate

TLC:Rf 0.14 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (s, 1H), 9.15 (br s, 2H), 8.83 (br s, 2H), 8.26 (d, J=1.8 Hz, 1H),8.17 (d, J=9.2 Hz, 1H), 7.95 (dd, J=8.0, 1.8 Hz, 1H), 7.73-7.67 (m, 5H),7.60-7.48 (m, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.28-7.24 (m, 1H), 4.05-3.90(m, 1H), 2.32 (s, 3H), 1.07 (d, J=6.8 Hz, 3H), 0.89 (s, 9H).

EXAMPLE 41(14)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(2,2-dimethylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.15 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.85 (s, 1H), 9.22 (brs, 2H), 8.97 (brs, 2H), 8.61 (brt, J=6.5 Hz, 1H),8.42 (d, J=2.0 Hz, 1H), 8.04 (dd, J=8.0,2.0 Hz, 1H), 7.93 (d, J=8.7 Hz,2H), 7.79 (d, J=8.7 Hz, 2H), 7.64 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.8 Hz,1H), 7.30 (d, J=8.0 Hz, 1H), 3.13 (d, J=6.5 Hz, 2H), 2.67 (s, 3H), 2.37(s, 3H), 0.91 (s, 9H).

EXAMPLE 41(15)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(2,2-dimethylpropyl)carbamoyl]benzoic acid

TLC:Rf 0.49 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,DMSO-d₆): δ 13.6 (brs, 1H), 9.01 (brs, 4H), 8.38 (brt, J=6.3 Hz, 1H),8.04 (d, J=1.5 Hz, 1H), 7.64 (dd, J=8.0, 1.5 Hz, 1H), 7.59 (s, 4H), 7.39(d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 3.05(d, J=6.3 Hz, 2H), 2.56 (s, 3H), 0.87 (s, 9H).

EXAMPLE 41(16)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(2,2-dimethylpropyl)carbamoyl]benzoic acid dihydrochioride

TLC:Rf 0.39 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,DMSO-d₆): δ 10.85 (s, 1H), 9.26 (brs, 2H), 9.03 (brs, 2H), 8.61 (brt,J=6.3 Hz, 1), 8.41 (d, J=1.8 Hz, 1H), 8.04 (dd, J=8.0, 1.8 Hz, 1H), 7.93(d, J=8.7 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.0 Hz, 1H), 7.55(d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 3.13 (d, J=6.3 Hz, 2H), 2.67(s, 3H), 0.91 (s, 9H).

EXAMPLE 41(17)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-methylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.33 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.5 (broad, 1H), 10.61 (s, 1H), 9.21 (brs, 2H), 8.92 (brs, 2H),8.70 (brt, J=6.0 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.02 (dd, J=8.0, 1.8Hz, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.65 (d, J=8.4Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.09 (s, 3H),3.11 (t, J=6.5 Hz, 2H), 2.34 (s, 3H), 1.94-1.80 (m, 1H), 0.90 (d, J=6.5Hz, 6H).

EXAMPLE 41(18)

2′-(4-amidinophenylcarbamoyl)-4-(1-methoxycarbonylcyclopentylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.21 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.15 (br s, 2H), 8.87 (s, 1H), 8.83 (br s, 2H), 8.30 (d,J=1.8 Hz, 1H), 7.97 (dd, J=8.0, 1.8 Hz, 1H), 7.73-7.68 (m, 5H),7.63-7.48 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.30-7.24 (m, 1H), 3.57 (s,3H), 2.32 (s, 3H), 2.20-2.00 (m, 4H), 1.80-1.60 (m, 4H).

EXAMPLE 41(19)

2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-hydroxymethyl-2-methylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.12 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 11.04(s, 1H), 9.23 (brs, 2H), 8.99 (brs, 2H), 8.88 (d, J=5.4 Hz, 1H), 8.70(s, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.07 (dd,J=8.0, 1.8 Hz, 1H), 7.90 (d, J=5.4 Hz, 1H), 7.77 (d, J=9.3 Hz, 2H), 7.73(d, J=9.3 Hz, 2H), 7.46 (d, J=8.0 Hz, 1H), 3.86-3.76 (m, 1H), 3.56-3.45(m, 2H), 2.36 (s, 3H), 1.98-1.82 (m, 1H), 0.90 (d, J=6.9 Hz, 3H), 0.86(d, J=6.9 Hz, 3H).

EXAMPLE 41(20)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1(S)-hydroxymethyl-2-methylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.19 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.85(s, 1H), 9.22 (brs, 2H), 8.97 (brs, 2H), 8.43 (d, J=1.8 Hz, 1H), 8.25(d, J=9.0 Hz, 1H), 8.06 (dd, J=8.0, 1.8 Hz, 1H), 7.93 (d, J=9.0 Hz, 2H),7.79 (d, J=9.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H),7.30 (d, J=8.0 Hz, 1H), 3.90-3.80 (m, 1H), 3.58-3.48 (m, 2H), 2.67 (s,3H), 2.37 (s, 3H), 2.01-1.86 (m, 1H), 0.92 (d, J=6.9 Hz, 3H), 0.89 (d,J=6.6 Hz, 3H).

EXAMPLE 41(21)

2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-hydroxymethyl-2-methylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.45 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ11.00 (s, 1H), 9.19 (s, 2H), 8.90 (s, 2H), 8.73 (dd, J=4.5, 1.8 Hz, 1H),8.44 (d, J=1.8 Hz, 1H), 8.25 (br.d, J=8.7 Hz, 1H), 8.08 (dd, J=8.0, 1.8Hz, 1H), 7.95 (d, J=8.7 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.80-7.65 (m,2H), 7.33 (d, J=8.0 Hz, 1H), 4.80-4.20 (br, 2H), 3.86 (m, 1H), 3.60-3.50(m, 2H), 2.34 Hz, 3H), 1.94 (like sextet, J=7.0 Hz, 1H), 0.93 (d, J=7.0Hz, 3H), 0.90 (d, J=7.0 Hz, 3H).

EXAMPLE 41(22)

2′-(4-amidinophenylcarbamoyl)-4-[(2-methoxycarbonyl-2,2-dimethylethyl)carbamoyl]-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.25 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,d₆-DMSO): δ 10.6 (s, 1H), 9.15 (br s, 2H), 8.83 (br s, 2H), 8.61 (t,J=6.3 Hz, 1H), 8.25 (d, J=1.5 Hz, 1H), 7.92 (dd, J=8.1, 1.5 Hz, 1H),7.72-7.68 (m, 5H), 7.65-7.50 (m, 2H), 7.32 (d, J=8.1 Hz, 1H), 7.27 (dd,J=7.2, 1.5 Hz, 1H), 3.58 (s, 3H), 3.42 (d, J=6.3 Hz, 2H), 2.31 (s, 3H),1.13 (s, 6H).

EXAMPLE 41(23)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1(S)-methoxycarbonyl-2-methylpropyl)carbamoyl]benzoicacid

TLC:Rf 0.39 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.51 (d, J=1.8 Hz, 1H), 8.03 (dd, J=8.0, 1.8 Hz, 1H), 7.88 (d,J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.61 (d, J=8.3 Hz, 1H), 7.52 (d,J=8.3 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 4.53 (d, J=6.9 Hz, 1H), 3.77 (s,3H), 2.70 (s, 3H), 2.37-2.21 (m, 1H), 1.06 (d, J=6.9 Hz, 3H), 1.04 (d,J=3H).

EXAMPLE 41(24)

2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-methoxycarbonyl-2-methylpropyl)carbamoyl]benzoicacid

TLC:Rf 0.39 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.73 (d, J=5.4 Hz, 1H), 8.51 (s, 1H), 8.42 (d, J=1.8 Hz, 1H),8.00 (dd, J=8.1, 1.8 Hz, 1H), 7.71 (s, 4H), 7.70 (d, J=5.4 Hz, 1H), 7.44(d, J=8.1 Hz, 1H), 4.48 (d, J=6.9 Hz, 1H), 3.74 (s, 3H), 2.33-2.16 (m,1H), 1.03 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.6 Hz, 3H).

EXAMPLE 41(25)

2′-(4-amidino-3-hydroxyphenylcarbamoyl)-4-(2-methylpropylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.60 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 11.15(s, 1H), 10.39 (s, 1H), 8.79 (s, 2H), 8.66 (t, J=6.0 Hz, 1H), 8.61 (s,2H), 8.32 (d, J=1.8 Hz, 1H), 7.96 (dd, J=8.0, 1.8 Hz, 1H), 7.68 (dd,J=8.0, 1.8 Hz, 1H), 7.59-7.52 (m, 3H), 7.48 (d, J=8.0 Hz, 1H), 7.31 (d,J=8.0 Hz, 1H), 7.26 (dd, J=8.0, 1.8 Hz, 1H), 7.00 (dd, J=8.0, 1.8 Hz,1H), 3.10 (t, J=6.0 Hz, 2H), 2.34 (s, 3H), 1.86 (m, 1H), 0.89 (d, J=6.3Hz, 6H).

EXAMPLE 41(26)

2′-(4-amidino-3-hydroxyphenylcarbamoyl)-4-(1,2,2-trimethylpropylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.68 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 11.14(br.s, 1H), 10.42 (s, 1H), 8.79 (s, 2H), 8.54 (s, 2H), 8.29 (s, 1H),8.18 (d, J=9.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H),7.58-7.52 (m, 3H), 7.48 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.25(d, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 4.00 (m, 1H), 2.31 (s, 3H),1.09 (d, J=7.0 Hz, 3H), 0.91 (s, 9H).

EXAMPLE 41(27)

2′-(4-amidinophenylcarbamoyl)-4-(1,3-dimethylbutylcarbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.27 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 12.84(br, 1H), 10.53 (s, 1H), 9.15 (s, 2H), 8.82 (s, 2H), 8.34 (d, J=8.4 Hz,1H), 8.30 (d, J=1.5 Hz, 1H), 7.96, (dd, J=7.8, 1.5 Hz, 1H), 7.74 (dd,J=6.9, 1.5 Hz, 1H), 7.73 (s, 4H), 7.58 (dt, J=6.0, 1.8 Hz, 1H), 7.53(dt, J=7.8, 1.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H),4.13 (m, 1H), 2.35 (s, 3H), 1.68-1.48 (m, 2H), 1.24 (m, 1H), 1.13 (d,J=6.3 Hz, 3H), 0.8 (d, J=6.3 Hz, 6H)

EXAMPLE 41(28)

2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethyl-1(R)-cyclopentylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.30 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.0 (br, 1H), 10.54 (s, 1H), 9.14 (s, 2H), 8.83 (s, 2H), 8.27 (d,J=1.8 Hz, 1H), 8.19 (d, J=8.7 Hz, 1H), 7.95 (dd, J=9.7, 1.8 Hz, 1H),7.72 (m, 5H), 7.55 (td, J=7.8, 1.5 Hz, 1H), 7.54 (td, J=7.8, 1.5 Hz,1H), 7.31 (d, J=9.7 Hz, 1H), 7.26 (dd, J=7.8,1.5 Hz, 1H), 4.08 (q, J=8.7Hz, 1H), 2.33 (s, 3H), 1.90 (m, 1H), 1.74-1.40 (m, 5H), 0.98 (s, 3H),0.87 (s, 3H)

EXAMPLE 41(29)

2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-carboxy-2-methylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.60 (Ethyl acetate:Acetic acid:Water=3:1:0.5); NMR (d₆-DMSO): δ11.01 (s, 1H), 9.20 (br.s, 2H), 8.95 (br.s, 2H), 8.80-8.70 (m, 2H), 8.47(d, J=1.8 Hz, 1H), 8.10 (dd, J=7.8, 1.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 2H),7.77 (d, J=8.8 Hz, 2H), 7.80-7.65 (m, 2H), 7.35 (d, J=7.8 Hz, 1H),6.40-4.40 (br, 2H), 4.33 (t, J=7.4 Hz, 1H), 2.37 (s, 3H), 2.22 (likesextet, J=7.4 Hz, 1H), 0.99 (d, J=7.4 Hz, 3H), 0.98 (d, J=7.4 Hz, 3H).

EXAMPLE 41(30)

2-[3-(4-amidinophenylcarbamoyl)-2-furyl]-5-(2-methylpropylcarbamoyl)benzoicacid methanesulfonate

TLC:Rf 0.39 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 13.0(brs, 1H), 10.29 (s, 1H), 9.20 (brs, 2H), 8.89 (brs, 2H), 8.74 (brt,J=6.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.05 (dd, J=8.0, 2.0 Hz, 1H),7.91 (d, J=8.7 Hz, 2H), 7.89 (d, J=2.0 Hz, 1H), 7.79 (d, J=8.7 Hz, 2H),7.69 (d, J=8.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 3.11 (brt, J=6.5 Hz,2H), 2.33 (s, 3H), 1.94-1.79 (m, 1H), 0.90 (d, J=6.5 Hz, 6H).

EXAMPLE 41(31)

2-[2-(4-amidinophenylcarbamoyl)-3-thienyl]-5-(2-methylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.56 (Chloroform:Methanol:Water 7:3:0.3); NMR (d₆-DMSO): δ 12.9(brs, 1H), 10.18 (s, 1H), 9.18 (brs, 2H), 8.87 (brs, 2H), 8.67 (brt,J=6.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.00 (dd, J=8.0, 2.0 Hz, 1H),7.84 (d, J=5.0 Hz, 1H), 7.75 (d, J=9.3 Hz, 2H), 7.70 (d, J=9.3 Hz, 2H),7.41 (d, J=8.0 Hz, 1H), 7.11 (d, J=5.0 Hz, 1H), 3.09 (brt, J=6.5 Hz,2H), 2.32 (s, 3H), 1.92-1.78 (m, 1H), 0.89 (d, J=6.5 Hz, 6H).

EXAMPLE 41(32)

2′-(4-amidinophenylcarbamoyl)-4-[(1-methoxycarbonyl-1-methylethyl)carbamoyl]-2-biphenylcarboxylic acid

TLC:Rf 0.25 (Chloroform:Methanol:Acetic acid=20:2:1); NMR (300 MHz,DMSO-d₆): δ 12.82 (brs, 1H), 10.56 (s, 1H), 9.15 (s, 2H), 8.84 (s, 2H),8.82 (s, 1H), 8.31 (d, J=2.0 Hz, 1H), 7.98 (dd, J=8.1, 2.0 Hz, 1H), 7.74(s, 2H), 7.67 (dd, J=6.6, 2.0 Hz, 1H), 7.59 (dt, J=7.2, 2.0 Hz, 1H),7.53 (dt, J=7.2, 2.0 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.28 (dd, J=7.8,2.0 Hz, 1H), 3.59 (s, 3H), 2.34 (s, 3H), 1.47 (s, 6H).

EXAMPLE 41(33)

2′-(4-amidinophenylcarbamoyl)-4-(1(S)-carboxy-3-methylbutylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.56 (Chloroform:Methanol:Water=6:4:1); NMR (d₆-DMSO): δ 12.79(br, 2H), 10.54 (s, 1H), 9.14 (s, 2H), 8.8 1 (d, J=8.4 Hz, 1H), 8.77 (s,2H), 8.:35 (d, J=1.8 Hz, 1H), 8.01 (dd, J=7.8, 1.8 Hz, 1H), 7.73 7.70,(m, 5H), 7.63 (dt, J=7.8, 1.2 Hz, 1H), 7.54 (dt, J=6.6, 1.8 Hz, 1H),7.35 J=7.8 Hz, 1H), 7.29 (dd, J=6.6, 1.8 Hz, 1H), 4.45 (m, 1H),1.82-1.55 (m, 3H), 0.92 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.0 Hz, 3H)

EXAMPLE 41(34)

2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.35 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ11.00 (s, 1H), 9.18 (s, 2H), 8.86 (s, 2H), 8.73 (dd, J=4.8, 2.1 Hz, 1H),8.61 (br.t, J=6.6 Hz, 1H), 8.43 (d, J=1.8 Hz, 1H), 8.06 (dd, J=7.8, 1.8Hz, 1H), 7.95 (d, J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.80-7.65 (m,2H), 7.34 (d, J=7.8 Hz, 1H), 3.90-3.70 (br, 1H), 3.14 (d, J=6.6 Hz, 2H),2.34 (s, 3H), 0.92 (s, 9H).

EXAMPLE 41(35)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.40 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.9-12.5 (broad, 1H), 10.61 (s, 1H), 9.19 (brs, 2H), 8.90 (brs, 2H),8.59 (brt, J=6.3 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.02 (dd, J=8.0, 1.8Hz, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.65 (d, J=8.4Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.09 (s, 3H),3.13 (brd, J=6.3 Hz, 2H), 2.34 (s, 3H), 0.91 (s, 9H).

EXAMPLE 41(36)

2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethyl-1(S)-cyclopentylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.30 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.6 (br, 1H), 10.54 (s, 1H), 9.13 (s, 2H), 8.80 (s, 2H), 8.27 (d,J=1.8 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 7.95 (dd, J=8.1, 1.8 Hz, 1H),7.72 (m, 4H), 7.69 (dd, J=6.9, 1.2 Hz, 1H), 7.57 (td, J=6.9, 1.2 Hz,1H), 7.52 (td, J=6.9, 1.2 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.26 (dd,J=6.9, 1.2 Hz, 1H), 4.08 (q, J=8.7 Hz, 1H), 2.31 (s, 3H), 1.90 (m, 1H),1.80-1.40 (m, 5H), 0.97 (s, 3H), 0.87 (s, 3H).

EXAMPLE 41(37)

2-[3-(4-amidinophenylcarbamoyl)-2-thienyl]-5-(2,2-dimethylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.21 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.2-12.6 (br, 1H), 10.31 (s, 1H), 9.16 (s, 2H), 8.82 (s, 2H), 8.59(br.t, J=6.3 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.01 (dd, J=8.0, 1.8 Hz,1H), 7.82 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.73 (d, J=5.4 Hz,1H), 7.64 (d, J=5.4 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 3.12 (d, J=6.3 Hz,2H), 2.32 (s, 3H), 0.90 (s, 9H).

EXAMPLE 41(38)

2-[2-(4-amidinophenylcarbamoyl)-3-thienyl]-5-(2,2-dimethylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.21 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.4 (br, 1H), 10.18 (s, 1H), 9.16 (s, 2H), 8.84 (s, 2H), 8.57(br.t, J=6.6 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.01 (dd, J=8.0, 1.8 Hz,1H), 7.84 (d, J=5.1 Hz, 1H), 7.74 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz,2H), 7.42 (d, J=8.0 Hz, 1H), 7.12 (d, J=5.1 Hz, 1H), 3.12 (d, J=6.6 Hz,2H), 2.32 (s, 3H), 0.90 (s, 9H).

EXAMPLE 41(39)

2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.60 (Chloroform:Methanol:Water=a7:3:0.3); NMR (d₆-DMSO): δ 10.96(s, 1H), 9.21 (s, 2H), 8.93 (s, 2H), 8.86 (d, J=5.1 Hz, 1H), 8.66 (s,1H), 8.62 (t, J=6.2 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.06 (dd, J=8.1,2.1 Hz, 1H), 7.85 (d, J=5.1 Hz, 1H), 7.76 (s, 4H), 7.46 (d, J=8.1 Hz,1H), 3.12 (d, J=6.2 Hz, 1H), 2.37 (s, 3H), 0.91 (s, 9H).

EXAMPLE 41(40)

2-[2-(4-amidinophenylcarbamoyl)-5-methyl-3-thienyl]-5-(2,2-dimethylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.61 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.87 (br, 1H), 9.97 (s, 1H), 9.15 (s, 2H), 8.80 (s, 2H), 8.56 (t, J=6.6Hz, 1H), 8.28 (d, J=1.5 Hz, 1H), 8.00 (dd, J=8.0, 1.5 Hz, 1H), 7.73 (d,J=9.0 Hz, 2H), 7.67 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 1H), 6.85 (s,1H), 3.11 (d, J=6.6 Hz, 2H), 2.54 (s, 3H), 2.31 (s, 3H), 0.90 (s, 9H).

EXAMPLE 41(41)

2′-(4-amidinophenylcarbamoyl)-4′-amino-4-(2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylicacid dimethanesulfonate

TLC:Rf 0.35 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.49(s, 1H), 9.13 (s, 2H), 8.78 (s, 2H), 8.50 (br.t, J=6.3 Hz, 1H), 8.24 (d,J=1.8 Hz, 1H), 7.92 (dd, J=8.0,1.8 Hz, 1H), 7.71 (s, 4H), 7.29 (d, J=8.0Hz, 1H), 7.11-7.01 (m, 3H), 3.10 (d, J=6.3 Hz, 2H), 2.35 (s, 6H), 0.89(s, 9H).

EXAMPLE 41(42)

2-[2-(4-amidinophenylcarbamoyl)-5-methyl-3-furyl]-5-(2,2-dimethylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.29 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.4 (br, 1H), 10.42 (s, 1H), 9.18 (s, 2H), 8.87 (s, 2H), 8.57(br.t, J=6.6 Hz, 1H), 8.33 (d, J=1.5 Hz, 1H), 8.00 (dd, J=7.8, 1.5 Hz,1H), 7.93 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.45 (d, J=7.8 Hz,1H), 6.43 (s, 1H), 3.13 (d, J=6.6 Hz, 2H), 2.46 (s, 3H), 2.33 (s, 3H),0.91 (s, 9H).

EXAMPLE 41(43)

2-[4-(4-amidinophenylcarbamoyl)-2-methyl-pyrimidin-5-yl]-5-(2,2-dimethylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.40 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ11.02 (s, 1H), 9.20 (brs, 2H), 8.85 (brs, 2H), 8.73 (s, 1H), 8.62 (brt,J=6.5 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H),7.91 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 1H),3.14 (d, J=6.5 Hz, 2H), 2.83 (s, 3H), 2.30 (s, 3H), 0.91 (s, 9H).

EXAMPLE 41(44)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(1(S)-morpholinocarbonyl-3-methylbutylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.78 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.84 (s, 1H), 9.20 (s, 2H), 8.93 (s, 2H), 8.90 (d, J=8.1 Hz, 1H), 8.46(d, J=1.8 Hz, 1H), 8.08 (dd, J=8.1, 1.8 Hz, 1H), 7.83 (d, J=9.0 Hz, 2H),7.78 (d, J=9.0 Hz, 2H), 7.64 (d, J=8.1 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H),7.31 (d, J=8.1 Hz, 1H), 4.97 (m, 1H), 4.46 (br, 1H), 3.7-3.4 (m, 8H),2.67 (s, 3H), 2.36 (s, 3H), 1.8-1.6 (m, 2H), 1.47 (m, 1H), 0.91 (d,J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H).

EXAMPLE 41(45)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(1(S)-methoxymethyl-2,2-dimethylpropylcarbamoyl)benzoicacid methanesulfonate

TLC:Rf 0.45 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.8 (s, 1H), 9.19 (br s, 2H), 8.84 (br s, 2H), 8.41 (d, J=1.8 Hz, 1H),8.27 (d, J=9.3 Hz, 1H), 8.04 (dd, J=8.1, 1.8 Hz, 1H), 7.93 (d, J=9.0 Hz,2H), 7.77 (d, J=9.0 Hz, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.56 (d, J=7.8 Hz,1H), 7.30 (d, J=8.1 Hz, 1H), 4.10 (dt, J=9.3, 3.3 Hz, 1H), 3.70-3.40 (m,2H), 3.23 (s, 3H), 2.67 (s, 3H), 2.32 (s, 3H), 0.93 (s, 9H).

EXAMPLE 41(46)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(1(S)-methoxymethyl-2,2-dimethylpropylcarbamoyl)benzoicacid methanesulfonate

TLC:Rf 0.48 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.18 (br s, 2H), 8.80 (br s, 2H), 8.40 (d, J=2.1 Hz, 1H),8.26 (d, J=9.3 Hz, 1H), 8.02 (dd, J=8.1, 2.1 Hz, 1H), 7.90 (d, J=9.0 Hz,2H), 7.77 (d, J=9.0 Hz, 2H), 7.65 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.1 Hz,1H), 7.13 (d, J=8.1 Hz, 1H), 4.15-4.05 (m, 1H), 4.09 (s, 3H), 3.59-3.46(m, 2H), 3.23 (s, 3H), 2.30 (s, 3H), 0.93 (s, 9H).

EXAMPLE 41(47)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(2,2-dimethylpropyloxycarbonyl)benzoic acid methanesulfonate

TLC:Rf 0.28 (Chloroform:Methanol:Acetic acid=20:2:1); NMR (d₆-DMSO): δ10.86 (s, 1H), 9.20 (s, 2H), 8.62 (brs, 2H), 8.54 (d, J=1.8 Hz, 1H),8.17, (dd, J=8.4, 1.8 Hz, 1H), 7.94 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7Hz, 2H), 7.58 (d, J=7.8 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.39 (d, J=7.8Hz, 1H), 4.05 (s, 2H), 2.70 (s, 3H), 2.37 (s, 3H), 1.04 (s, 9H).

EXAMPLE 41(48)

2-[2-(4-amidino-3-fluorophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.44 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ11.0 (s, 1H), 9.30 (br s, 2H), 9.17 (br s, 2H*3/5), 9.10 (br s, 2H*2/5),8.60 (t, J=6.3 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 8.05 (dd, J=7.8, 2.1 Hz,1H), 7.85 (dd, J=14, 2.1 Hz, 1H), 7.74 (dd, J=9.0, 2.1 Hz, 1H),7.65-7.60 (m, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.30(d, J=8.1 Hz, 1H), 3.13 (d, J=6.3 Hz, 2H), 2.67 (s, 3H), 2.36 (s,3H*3/5), 2.33 (s, 3H*2/5), 0.91 (s, 9H).

EXAMPLE 41(49)

4-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]isophthalic acidmethanesulfonate

TLC:Rf 0.3 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.83 (s, 1H), 9.20 (s, 2H), 8.90 (s, 2H), 8.48 (d, J=1.8 Hz, 1H), 8.10(dd, J=8.1, 1.8 Hz, 1H), 7.91 (d, J=8.7 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H),7.64 (d, J=7.8 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H),2.68 (s, 3H), 2.35 (s, 3H).

EXAMPLE 41(50)

2′-(4-amidinophenylcarbamoyl)-5′-amino-4-(2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylicacid dimethanesulfonate

TLC:Rf 0.42 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.24(s, 1H), 9.10 (s, 2H), 8.80 (s, 2H), 8.51 (br.t, J=6.0 Hz, 1H), 8.27 (d,J=2.0 Hz, 1H), 7.94 (dd, J=8.0,2.0 Hz, 1H), 7.69 (s, 4H), 7.58 (d, J=8.0Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.64 (s, 1H),3.10 (d, J=6.0 Hz, 2H), 2.38 (s, 6H), 0.89 (s, 9H).

EXAMPLE 41(51)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(1,1,3,3-tetramethylbutylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.48 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d-DMSO): δ10.84 (s, 1H), 9.21 (brs, 2H), 8.94 (brs, 2H), 8.31 (d, J=1.8 Hz, 1H),7.95 (dd, J=8.0, 1.8 Hz, 1H), 7.92 (d, J=9.0 Hz, 2H), 7.89 (brs, 1H),7.79 (d, J=9.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H),7.26 (d, J=8.0 Hz, 1H), 2.67 (s, 3H), 2.36 (s, 3H), 1.87 (s, 2H), 1.43(s, 6H), 0.98 (s, 9H).

EXAMPLE 41(52)

2-[2-(4-amidinophenylcarbamoyl)-5-methyl-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.50 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.93(s, 1H), 9.18 (s, 2H), 8.88 (s, 2H), 8.60 (br.t, J=6.2 Hz, 1H), 8.56 (d,J=2.0 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.06 (dd, J=8.0,2.0 Hz, 1H), 7.95(d, J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.57 (d, J=2.0 Hz, 1H), 7.31(d, J=8.0 Hz, 1H), 3.14 (d, J=6.2 Hz, 2H), 2.44 (s, 3H), 2.36 (s, 3H),0.92 (s, 9H).

EXAMPLE 41(53)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[5-(1-methylethyl)-2,2-dimethyidioxan-5-yl]carbamoyl]benzoicacid hydrochloride

TLC:Rf 0.40 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.8-12.5 (br, 1H), 9.24 (s, 2H), 9.07 (s, 2H), 8.33 (d, J=1.8 Hz, 1H),8.03 (s, 1H), 7.95 (dd, J=8.1, 1.8 Hz, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.78(d, J=8.7 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.10(d, J=8.4 Hz, 1H), 4.14 (d, J=12.0 Hz, 2H), 4.08 (s, 3H), 3.93 (d,J=11.7 Hz, 2H), 2.39 (m, 1H), 1.33 (s, 3H), 1.29 (s, 3H), 0.93 (d, J=7.2Hz, 6H).

EXAMPLE 41(54)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[1(S)-(4-ethoxycarbonyloxazol-2-yl)-3-methylbutyl)carbamoyl]benzoic acid

TLC:Rf 0.57 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.52 (d, J=1.8 Hz, 1H), 8.03 (dd, J=8.0, 1.8 Hz, 1H), 7.85 (d,J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 1H), 7.33 (d,J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 5.45 (dd, J=9.3, 6.0 Hz, 1H),4.34 (q, J=7.2 Hz, 2H), 4.12 (s, 3H), 2.07-1.87 (m, 2H), 1.82-1.68 (m,1H), 1.35 (t, J=7.2 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H), 1.01 (d, J=6.9 Hz,3H).

EXAMPLE 41(55)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-N-hydroxycarbamoyl)-3-methylbutylcarbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.39 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.77(s, 1H), 10.61 (s, 1H), 9.20 (s, 2H), 8.86 (s, 2H), 8.73 (d, J=7.8 Hz,1H), 8.47 (d, J=1.8 Hz, 1H), 8.08 (dd, J=7.8, 1.8 Hz, 1H), 7.91 (d,J=9.0 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.65 (d, J=8.1 Hz, 1H), 7.30 (d,J=7.8 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 4.49 (m, 1H), 4.11 (s, 3H), 2.35(s, 3H), 1.80-1.60 (m, 2H), 1.51 (m, 1H), 0.93 (d, J=6.6 Hz, 3H), 0.89(d, J=6.3 Hz, 3H).

EXAMPLE 41(56)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)-4-methylbenzoic acid methanesulfonate

TLC:Rf 0.20 (Chloroform:Methanol:Acetic acid=20:2:1); NMR (d₆-DMSO): δ10.59 (s, 1H), 9.21 (s, 2H), 8.90 (s, 2H), 8.45 (br.t, J=6.6 Hz, 1H),7.93 (d, J=9.0 Hz, 2H), 7.90 (s, 1H), 7.80 (d, J=9.0 Hz, 2H), 7.59 (d,J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.09 (s, 1H), 4.11 (s, 3H), 3.11(d, J=6.6 Hz, 2H), 2.40 (s, 6H), 0.94 (s, 9H).

EXAMPLE 41(57)

4-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]isophthalic acidmethanesulfonate

TLC:Rf 0.20 (Chloroform:Methanol:Acetic acid=3:1:1); NMR (d₆-DMSO): δ10.61 (s, 1H), 9.18 (s, 2H), 8.75 (s, 2H), 8.50 (d, J=1.8 Hz, 1H), 8.10(dd, J=8.0, 1.8 Hz, 1H), 7.91 (d, J=8.7 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H),7.67 (d, J=8.6 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H),4.11 (s, 3H), 2.32 (s, 3H).

EXAMPLE 41(58)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(1(S)-hydroxymethyl-3-methylbutylcarbamoyl)-4-methylbenzoicacid methanesulfonate

TLC:Rf 0.25 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.9-12.5 (broad, 1H), 10.60 (s, 1H), 9.19 (brs, 2H), 8.86 (brs, 2H),8.41 (d, J=2.0 Hz, 1H), 8.25 (brd, J=8.4 Hz, 1H), 8.02 (dd, J=8.0, 2.0Hz, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.64 (d, J=8.4Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.15-4.05 (m,1H), 4.09 (s, 3H), 3.47-3.32 (m, 2H), 2.32 (s, 3H), 1.72-1.56 (m, 1H),1.55-1.30 (m, 2H), 0.90 (d, J=6.6 Hz, 3H), 0.89 (d, J=6.6 Hz, 3H).

EXAMPLE 41(59)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(4,4-dimethyloxolan-3(S)-yl)carbamoyl]-4-methylbenzoicacid methanesulfonate

TLC:Rf 0.25 (Chloroform:Methanol:Acetic acid 10:2:1); NMR (d₆-DMSO): δ12.9-12.6 (broad, 1H), 10.61 (s, 1H), 9.18 (brs, 2H), 8.84 (brs, 2H),8.55 (brd, J=8.4 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.03 (dd, J=8.0, 2.0Hz, 1H), 7.89 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.65 (d, J=8.4Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.40-4.32 (m,1H), 4.09 (s, 3), 3.69 (dd, J=9.0, 6.0 Hz, 1H), 3.53 (d, J=5.4 Hz, 1H),3.48 (d, J=5.4 Hz, 1H), 2.31 (s, 3H), 1.10 (s, 3H), 0.96 (s, 3H).

EXAMPLE 41(60)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(1(R),2,2-trimethyl propylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.40 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.9-12.5 (broad, 1H), 10.61 (s, 1H), 9.20 (brs, 2H), 8.90 (brs, 2H),8.37 (d, J=1.8 Hz, 1H), 8.21 (brd, J=9.0 Hz, 1H), 8.00 (dd, J=8.0, 1.8Hz, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.63 (d, J=8.4Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.09 (s, 3H),4.06-3.96 (m, 1H), 2.33 (s, 3H), 1.10 (d, J=6.6 Hz, 3H), 0.92 (s, 9H).

EXAMPLE 41(61)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(R)-2,2-dimethylcyclopentyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.42 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.9-12.5 (broad, 1H), 10.61 (s, 1H), 9.20 (brs, 2H), 8.89 (brs, 2H),8.38 (d, J=1.8 Hz, 1H), 8.22 (brd, J=8.7 Hz, 1H), 8.01 (dd, J=8.0, 1.8Hz, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.64 (d, J=8.4Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.16-4.08 (m,1H), 4.09 (s, 3H), 2.32 (s, 3H), 2.00-1.88 (m, 1H), 1.83-1.42 (m, 5H),1.00 (s, 3H), 0.90 (s, 3H).

EXAMPLE 41(62)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-methylaminomethyl-3-methylbutyl)carbamoyl]benzoic acid dimethanesulfonate

TLC:Rf 0.17 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.75 (br, 1H), 10.62 (s, 1H), 9.21 (s, 2H), 8.91 (s, 2H), 8.57 (d,J=8.7 Hz, 1H), 8.60-8.40 (br, 2H), 8.48 (d, J=1.7 Hz, 1H), 8.09 (dd.J=8.0, 1.7 Hz, 1H), 7.91 (d, J=9.0 Hz, 2H), 7.81 (d, J=9.0 Hz, 2H), 7.63(d, J=8.7 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 4.43(m, 1H), 4.12 (3H), 3.20-3.00 (m, 2H), 2.60 (t, J=5.4 Hz, 3H), 2.35 (s,6H), 1.71-1.52 (m, 2H), 1.33 (m, 1H), 0.93 (d, J=6.3 Hz, 3H), 0.92 (d,J=6.3 Hz, 3H).

EXAMPLE 41(63)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(4,4-dimethyl-2-oxooxolan-3(S)-yl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.36 (Chloroform:Methanol:Acetic acid 10:2:1); NMR (d₆-DMSO): δ12.9-12.6 (broad, 1H), 10.62 (s, 1H), 9.19 (brs, 2H), 9.05 (brd, J=9.0Hz, 1H), 8.86 (brs, 2H), 8.50 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8Hz, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.67 (d, J=8.4Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 4.99 (d, J=9.0Hz, 1H), 4.16 (d, J=9.0 Hz, 1H), 4.10 (s, 3H), 4.08 (d, J 9.0 Hz, 1H),2.32 (s, 3H), 1.15 (s, 3H), 1.02 (s, 3H).

EXAMPLE 41(64)

2-[2-(4-amidinophenylcarbamoyl)-3-thienyl]-5-[(1(S)-acetyloxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.58 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.8-12.0 (br, 1H), 10.24 (s, 1H), 9.17 (s, 2H), 8.86 (s, 2H), 8.34 (d,J=8.4 Hz, 1H), 8.29 (d, J=1.8 Hz, 1H), 8.00 (dd, J=8.4, 1.8 Hz, 1H),7.84 (d, J=5.1 Hz, 1H), 7.74 (like s, 4H), 7.42 (d, J=8.4 Hz, 1H), 7.11(d, J=5.1 Hz, 1H), 4.34 (dd, J=10.2, 1.6 Hz, 1H), 4.13 (dd, J=10.2, 1.6Hz, 1H), 4.06 (t, J=10.2 Hz, 1H), 2.33 (s, 3H), 1.93 (s, 3H), 0.94 (s,9H).

EXAMPLE 41(65)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[4-carboxy-4-(2-methyl-2-propenyl)piperidinyl]carbonyl]benzoicacid methanesulfonate

TLC:Rf 0.37 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.19 (br s, 2H), 8.85 (br s, 2H), 7.91-7.88 (m, 3H), 7.78(d, J=8.7 Hz, 2H), 7.67 (d, J=8.1 Hz, 1H), 7.58 (dd, J=8.1, 1.8 Hz, 1H),7.27 (d, J=8.1 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 4.81 (s, 1H), 4.72 (s,1H), 4.30-4.10 (m, 2H*1/2, each of isomers), 4.09 (s, 3H), 3.60-3.40 (m,2H*1/2, each of isomers), 3.40-3.00 (m, 2H), 2.31 (s, 3H), 2.30 (s, 2H),2.10-1.90 (m, 2H), 1.66 (s, 3H), 1.50-1.30 (m, 2H).

EXAMPLE 41(66)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[1(S)-[N-methyl-N-(1-iminoethyl)aminomethyl]-3-methylbutyl]benzoicacid dimethanesulfonate

TLC:Rf 0.42 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (D₂O): δ 8.13(d, J=1.8 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.70(d, J=8.7 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 1H), 7.13(d, J=8.4 Hz, 1H), 4.73 (m, 1H), 4.03 (s, 3H), 3.62 and 3.57 (d, J=7.5Hz, 1H), 3.21 and 3.14 (s, 3H), 2.75 (s, 6H), 2.25 and 2.18 (s, 3H),1.76-1.54 (m, 2H), 1.39 (m, 1H), 0.92-0.85 (m, 6H).

EXAMPLE 41(67)

2′-(4-amidinophenylcarbamoyl)-4′-amino-4-(1(R), 2,2-trimethylpropylcarbamoyl)-2-biphenylcarboxylic acid dimethanesulfonate

TLC:Rf 0.52 (Chloroform:Methanol:Water 7:3:0.3); NMR (d₆-DMSO): δ 10.55(s, 1H), 9.14 (s, 2H), 8.85 (s, 2H), 8.24 (d, J=2.0 Hz, 1H), 8.15 (br.d,J=6.3 Hz, 1H), 7.93 (dd, J=8.0,2.0 Hz, 1H), 7.74 (d, J=9.0 Hz, 2H), 7.70(d, J=9.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.29 (s, 1H), 7.17 (s, 2H),3.98 (m, 1H), 2.37 (s, 6H), 1.08 (d, J=7.0 Hz, 3H), 0.90 (s, 9H).

EXAMPLE 41(68)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[1-(2,2-dimethylpropyl)tetrazol-5-yl]benzoic acid methanesulfonate

TLC:Rf 0.24 (Chloroform:Methanol:Acetic acid=10:1:0.2); NMR (d₆-DMSO): δ13.2-12.3 (br, 1H), 10.62 (s, 11H), 9.19 (s, 2H), 8.88 (s, 2H), 8.27 (d,J=1.8 Hz, 1H), 7.99 (dd, J=7.8, 1.8 Hz, 1H), 7.90 (d, J=9.0 Hz, 2H),7.79 (d, J=9.0 Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H),7.15 (d, J=8.4 Hz, 1H), 4.38 (s, 2H), 4.10 (s, 3H), 2.32 (s, 3H), 0.80(s, 9H).

EXAMPLE 41(69)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[1-(1-iminoethyl)-4-(2-methylpropyl)piperidin-4-yl]carbamoyl]benzoicacid dimethanesulfonate

TLC:Rf 0.48 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.20 (br s, 2H), 9.08 (br s, 1H), 8.89 (br s, 2H), 8.53(br s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.08 (s, 1H), 8.02 (dd, J=8.1, 1.8Hz, 1H), 7.90 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.7Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 4.10 (s, 3H),3.93-3.76 (m, 2H), 3.40-3.20 (m, 2H), 2.61-2.44 (m, 2H), 2.31 (s, 6H),2.26 (s, 3H), 1.74-1.49 (m, 5H), 0.90 (d, J=6.0 Hz, 6H).

EXAMPLE 41(70)

3-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-6-[(1(R),2,2-trimethyl propyl)carbamoyl]-2-pyridinecarboxylic acidmethanesulfonate

TLC:Rf 0.40 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 12.95(br.s, 1H), 10.65 (s 1H), 9.20 (s, 2H), 8.89 (s, 2H), 8.69 (d, J=10.0Hz, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.90 (d, J=9.0Hz, 2H), 7.78 (d, J=9.0 Hz, 2H ), 7.74 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0Hz, 1H), 4.12 (s, 3H), 4.02 (dq, J=10.0,7.2 Hz, 1H), 2.33 (s, 3H), 1.17(d, J=7.2 Hz, 3H), 0.94 (s, 9H).

EXAMPLE 41(71)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(t-butylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.50 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.60 (s, 1H), 9.20 (s, 2H), 8.88 (s, 2H), 8.32 (d, J=1.8 Hz, 1H), 8.00(s, 1H), 7.95 (dd, J=7.8,1.8 Hz, 1H), 7.88 (di J=9.3 Hz, 2H), 7.78 (d,J=9.3 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.11 (d,J=8.4 Hz, 1H), 4.09 (s, 3H), 2.32 (s, 3H), 1.40 (s, 9H).

EXAMPLE 41(72)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2,2-trichloroethylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.40 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.81 (s, 1H), 10.62 (s, 1H), 9.56 (t, J=6.4 Hz, 1H), 9.20 (s, 2H), 8.86(s, 2H), 8.49 (d, J=1.8 Hz, 1H), 8.04 (dd, J=8.0, 1.8 Hz, 1H), 7.90 (d,J=9.2 Hz, 2H), 7.79 (d, J=9.2 Hz, 2H), 7.67 (d, J=8.6 Hz, 1H), 7.35 (d,J=8.0 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 4.42 (d, J=6.0 Hz, 2H), 4.10 (s,3H), 2.31 (s, 3H).

EXAMPLE 41(73)

2-[3-(4-amidinophenylcarbamoyl)-2-thienyl]-6-(t-butylcarbamoyl)-2-pyridinecarboxylic acid methanesulfonate

TLC:Rf 0.15 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.05 (br.s, 1H), 10.41 (s 1H), 9.17 (s, 2H), 8.82 (s, 2H), 8.31 (s,1H), 8.19 (d, J=8.0 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.84 (d, J=9.0 Hz,2H), 7.82 (d, J=5.4 Hz, 1H), 7.75 (d, J=9.0 Hz, 2H), 7.73 (d, J=5.4 Hz,1H), 2.31 (s, 3H), 1.44 (s, 9H).

EXAMPLE 41(74)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2,2-trifluoroethcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.30 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 12.79(brs, 1H), 10.62 (s, 1H), 9.34 (t, J=6.3 Hz, 1H), 9.19 (s, 2H), 8.81 (s,2H), 8.48 (d, J=1.8 Hz, 1H), 8.08 (dd, J=7.8, 1.8 Hz, 1H), 7.91 (d,J=8.7 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.36 (d,J=7.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 4.22-4.10 (m, 2H), 4.11 (s, 3H),2.32 (s, 3H).

EXAMPLE 41(75)

2-[2-[(2-amidinopyrimidin-5-yl)carbamoyl]-6-methoxy-3-pyridyl]-5-(2,2-dimethylpropyicarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.38 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.6 (br, 1H), 11.05 (s, 1H), 9.59 (s, 2H), 9.35 (s, 2H), 9.29 (s,2H), 8.59 (t, J=6.0 Hz, 1H), 8.41 (d, J=1.5 Hz, 1H), 8.04 (dd, J=8.0,1.5 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.18 (d,J=8.7 Hz, 1H), 4.11 (s, 3H), 3.13 (d, J=6.0 Hz, 2H), 2.29 (s, 3H), 0.91(s, 9H).

EXAMPLE 41(76)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[1(S)-(2-aminoethyl)-3-methylbutylcarbamoyl]benzoicacid dimethanesulfonate

TLC:Rf 0.17 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 12.80(br.s, 1H), 10.62 (s 1H), 9.19 (s, 2H), 8.90 (s, 2H), 8.51 (d, J=9.0 Hz,1H), 8.42 (d, J=2.0 Hz, 1H), 8.04 (dd, J=8.0,2.0 Hz, 1H), 7.90 (d, J=9.0Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.69 (br.s, 3H), 7.64 (d, J=8.4 Hz,1H), 7.32 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H ), 4.15 (m, 1H), 4.10(s, 3H), 2.90-2.78 (m, 2H), 2.34 (s, 6H), 1.83-1.60 (m, 4H), 1.27 (m,1H), 0.90 (d, J=6.8 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H).

EXAMPLE 41(77)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2,2-diethylbutyloxy)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.80 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 12.86(s, 1H), 10.63 (s, 1H), 9.20 (s, 2H), 8.86 (s, 2H), 8.50 (d, J=1.5 Hz,1H), 8.11 (dd, J=8.1, 1.5 Hz, 1H), 7.91 (d, J=9.0 Hz, 2H), 7.80 (d,J=9.0 Hz, 2H), 7.68 (d, J=8.7 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.15 (d,J=8.7 Hz, 1H), 4.12 (s, 3H), 4.10 (s, 2H), 2.33 (s, 3H), 1.36 (q, J=7.5Hz, 6H), 0.82 (t, J=7.5 Hz, 9H).

EXAMPLE 41(78)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2,2-dimethyl-3-hydroxypropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.10 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.19 (br s, 2H), 8.82 (br s, 2H), 8.62 (t, J=5.8 Hz, 1H),8.40 (d, J=1.8 Hz, 1H), 8.02 (dd, J=8.2, 1.8 Hz, 1H), 7.90 (d, J=9.2 Hz,2H), 7.78 (d, J=9.2 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.2 Hz,1H, 7.13 (d, J=8.4 Hz, 1H), 4.10 (s, 3H), 3.19 (d, J=6.2 Hz, 2H), 3.15(s, 2H), 2.31 (s, 3H), 0.85 (s, 6H).

EXAMPLE 41(79)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2,2-diethylbutyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.31 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.62 (s, 1H), 9.21 (s, 2H), 8.89 (s, 2H), 8.36 (d, J=1.8 Hz, 1H), 8.24(t, J=6.6 Hz, 1H), 7.99 (dd, J=8.4, 1.8 Hz, 1H), 7.91 (d, J=9.0 Hz, 2H),7.80 (d, J=9.0 Hz, 2H), 7.65 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H),7.13 (d, J=8.4 Hz, 1H), 4.11 (s, 3H), 3.18 (d, J=6.6 Hz, 2H), 2.34 (s,3H), 1.24 (q, J=7.5 Hz, 6H), 0.81 (t, J=7.5 Hz, 9H).

EXAMPLE 41(80)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[((1-hydroxymethyl)cyclobutylmethyl)carbamoyl]benzoic acid methanesulfonate

TLC Rf 0.16 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.17 (br s, 2H), 8.77 (br s, 2H), 8.66 (t, J=6.0 Hz, 1H),8.41 (d, J=2.1 Hz, 1H), 8.02 (dd, J=7.8, 2.1 Hz, 1H), 7.90 (d, J=8.7 Hz,2H), 7.77 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.1 Hz, 1H), 7.31 (d, J=7.8 Hz,1H), 7.12 (d, J=8.1 Hz, 1H), 4.09 (s, 3H), 3.41-3.36 (m, 4H), 2.29 (s,3H), 1.90-1.70 (m, 6H).

EXAMPLE 41(81)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-ethyl-2-hydroxymethylbutyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.24 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.18 (br s, 2H), 8.80 (br s, 2H), 8.49 (t, J=6.0 Hz, 1H),8.38 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.1, 2.1 Hz, 1H), 7.90 (d, J=8.7 Hz,2H), 7.77 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.1 Hz,1H), 7.13 (d, J=8.4 Hz, 1H), 4.10 (s, 3H), 3.20-3.18 (m, 4H), 2.30 (s,3H), 1.22 (septet, J=6.6 Hz, 4H), 0.81 (t, J=6.6 Hz, 6H).

EXAMPLE 41(82)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[((1-hydroxymethyl)cyclopentylmethyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.20 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,d₆-DMSO): δ 10.6 (s, 1H), 9.19 (br s, 2H), 8.84 (br s, 2H), 8.67 (t,J=6.3 Hz, 1H), 8.40 (d, J=1.5 Hz, 1H), 8.02 (dd, J=7.8, 1.5 Hz, 1H),7.90 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H),7.31 (d, J=7.8 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.10 (s, 3H), 3.36-3.22(m, 4H), 2.30 (s, 3H), 1.57-1.38 (m, 8H).

EXAMPLE 41(83)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-propyl-2-hydroxymethylpentyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.50 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,d₆-DMSO): δ 12.8-12.3 (brd, 1H), 10.61 (s, 1H), 9.19 (s, 2H), 8.83 (s,2H), 8.50 (t, J=5.7 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.00 (dd, J=8.1,1.8 Hz, 1H), 7.90 (d, J=8.7 Hz, 2H), 7.71 (d, J=8.7 Hz, 2H), 7.65 (d,J=8.7 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.12 (d, J=8.7 Hz, 1H), 4.09 (s,3H), 3.21-3.18 (m, 4H), 2.31 (s, 3H), 1.18-1.02 (m, 8H), 0.86 (t, J=6.6Hz, 6H).

EXAMPLE 41(84)

2-(2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-(2-methylpropyl)-2-hydroxymethyl-4-methylpentyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.23 (Chloroform:Methanol:Acetic acid=10:2:1); NMR(300 MHz,DMSO-d₆) :δ 12.74 (br, 1H), 10.62:(s, 1H), 9.19 (s, 2H), 8.12 (s, 2H),8.42 (m, 1H), 8.37 (d, J=1.8 Hz, 1H), 7.97 (dd, J=8.1, 1.8 Hz, 1H), 7.91(d,J=9.0 Hz,2H), 7.79 (d, J=9.0 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.33(d, J=8.1 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 4.77 (br, 1H), 4.11 (s, 3H),2.32 (s, 3H), 1.82-1.70 (m, 2H), 1.40-1.20 (m, 4H), 0.92 (d, J=6.9 Hz,6H).

EXAMPLE 41(85)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1-hydroxymethylcyclopentyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.23 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,DMSO-d₆): δ 10.61 (s, 1H), 9.20 (s, 2H), 8.87 (s, 2H), 8.36 (d, J=1.8Hz, 1H), 7.99 (dd, J=8.4, 1.8 Hz, 1H), 7.98 (s, 1H), 7.91 (d, J=9.0 Hz,2H), 7.79 (d, J=9.0 Hz, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz,1H), 7.13 (d, J=8.4 Hz, 1H), 4.10 (s, 3H), 3.61 (s, 2H), 2.33 (s, 31),2.09-2.00 (m, 2H), 1.80-1.62 (m, 4H), 1.62-1.54 (m, 2H).

EXAMPLE 41(86)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1-(2-methylpropyl)-1-hydroxymethyl-3-methylbutyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.23 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,DMSO-d₆): δ 10.59 (s, 1H), 9.16 (s, 2H), 8.77 (s, 2H), 8.28 (d, J=2.1Hz, 1H), 7.90 (dd, J=8.1, 2.1 Hz, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.76 (d,J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 1H), 7.46 (s, 1H), 7.25 (d, J=8.1 Hz,1H), 7.10 (d, J=8.7 Hz, 1H), 4.08 (s, 3H), 3.61 (s, 2H), 2.29 (s, 3H),1.87 (dd, J=13.8, 5.7 Hz, 2H), 1.80-1.68 (m, 2H), 1.59 (dd, J=13.8, 5.1Hz, 2H), 0.89 (d, J=6.6 Hz, 6H), 0.88 (dd, J=6.3 Hz, 6H).

EXAMPLE 41(87)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-(hydroxymethyl)-2(S)-methylbutyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.35 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,d₆-DMSO): δ 12.8-12.3 (brd, 1H), 10.60 (s, 1H), 9.18 (s, 2H), 8.82 (s,2H), 8.41 (d, J=1.8 Hz, 1H), 8.25 (d, J=8.7 Hz, 1H), 8.04 (dd, J=8.1,1.8 Hz, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.64 (d,J=8.1 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 4.09 (s,3H), 3.88 (m, 1H), 3.52 (m, 1H), 3.00 (m, 1H), 2.31 (s, 3H), 1.74 (m,1H), 1.50 (m, 1H), 1.18 (m, 1H), 0.90 (d, J=6.6 Hz, 3H), 0.86 (t, J=7.5Hz, 3H).

EXAMPLE 41(88)

2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-isopropyl-3-aminopropyl)carbamoyl benzoic acid dimethanesulfonate

TLC:Rf 0.60 (Ethyl acetate:Acetic acid:Water=3:3:1); NMR (300 MHz,d₆-DMSO): δ 12.8-12.3 (brd, 1H), 10.58 (s, 1H), 9.19 (s, 2H), 8.91 (s,2H), 8.45 (d, J=8.7 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.04 (dd, J=8.1,1.8 Hz, 1H), 7.88 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.72 (brd,2H), 7.61 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.19 (dd, J=19.8,6.9 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 4.56 (m, 2H), 3.83 (m, 1H),2.85-2.70 (m, 2H), 2.33 (s, 6H), 1.95-1.70 (m, 3H), 1.41 (t, J=6.9 Hz,3H), 0.94 (d, J=6.0 Hz, 3H), 0.92 (d, J=6.0 Hz, 3H).

EXAMPLE 41(89)

2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-(2-aminoethyl)-3-methylbutyl)carbamoyl]benzoicacid dimethanesulfonate

TLC:Rf 0.65 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (300 MHz,d₆-DMSO): δ 13.0-12.5 (broad, 1H), 10.57 (s, 1H), 9.20 (brs, 2H), 8.91(brs, 2H), 8.51 (brd, J=9.0 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.03 (dd,J=8.0, 1.8 Hz, 1H), 7.89 (d, J=9.0 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H),7.82-7.68 (broad, 3H), 7.62 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H),7.10 (d, J=8.4 Hz, 1H), 4.56 (brq, J=7.0 Hz, 2H), 4.21-4.28 (m, 1H),2.90-2.75 (m, 2H), 2.33 (s, 6H), 1.88-1.57 (m, 4H), 1.41 (t, J=7.0 Hz,3H), 1.34-1.22 (m, 1H), 0.91 (d, J=6.6 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

EXAMPLE 41(90)

2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-(2-aminoethyl)-2(S)-methylbutyl)carbamoyl]benzoicacid dimethanesulfonate

TLC:Rf 0.64 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (300 MHz,d₆-DMSO): δ 13.0-12.5 (broad, 1H), 10.57 (s, 1H), 9.20 (brs, 2H), 8.91(brs, 2H), 8.48 (brd, J=9.0 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.04 (dd,J=8.0, 1.8 Hz, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H),7.82-7.68 (broad, 3H), 7.62 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H),7.10 (d, J=8.4 Hz, 1H), 4.56 (brq, J=7.0 Hz, 2H), 3.98-3.85 (m, 1H),2.90-2.70 (m, 2H), 2.33 (s, 6H), 1.95-1.58 (m, 3H), 1.41 (t, J=7.0 Hz,3H), 1.24-1.08 (m, 1H), 0.91 (d, J=6.6 Hz, 3H), 0.89 (d, J=7.2 Hz, 3H).

EXAMPLE 42(1)-42(7)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 8 or Example 11, using a compoundprepared in Example 41(5), 41(18), 41(22), 41(23), 41(24), 41(32) or41(54).

EXAMPLE 42(1)

2′-(4-amidinophenylcarbamoyl)-4-[(1(S)-carboxymethyl-2,2-dimethylpropyl)carbamoyl]-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.41 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.6 (1H, s), 9.15 (2H, br s), 8.80 (2H, br s), 8.28 (1H, d, J=8.8 Hz),8.26 (1H, s), 7.92 (1H, d, J=6.0 Hz), 7.73-7.68 (5H, m), 7.60-7.48 (2H,m), 7.33-7.25 (2H, m), 4.29 (1H, t, J=8.8 Hz), 2.60-2.40 (2H, m), 2.30(3H, s), 0.89 (9H, s).

EXAMPLE 42 (2)

2′-(4-amidinophenylcarbamoyl)-4-(1-carboxycyclopentylcarbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.11 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (s, 1H), 9.15 (br s, 2H), 8.83 (br s, 2H), 8.72 (s, 1H), 8.29 (d,J=1.8 Hz, 1H), 7.96 (dd, J=7.8, 1.8 Hz, 1H), 7.73-7.68 (m, 5H),7.60-7.50 (m, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.28-7.24 (m, 1H), 2.31 (s,3H), 2.20-2.00 (m, 4H), 1.80-1.60 (m, 4H).

EXAMPLE 42 (3)

2′-(4-amidinophenylcarbamoyl)-4-[(2-carboxy-2,2-dimethylethyl)carbamoyl]-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.20 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (s, 1H), 9.16 (br s, 2H), 8.87 (br s, 2H), 8.53 (t, J=5.0 Hz, 1H),8.27 (d, J=2.0 Hz, 1H), 7.94 (dd, J=8.4, 2.0 Hz, 1H), 7.73-7.67 (m, 5H),7.58-7.52 (m, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.30-7.24 (m, 1H), 3.43 (d,J=5.0 Hz, 2H), 2.32 (s, 3H), 1.10 (s, 6H).

EXAMPLE 42(4)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyrdyl]-5-[(1(S)-carboxy-2-methylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.79 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ13.0-12.4 (broad, 2H), 10.84 (s, 1H), 9.17 (brs, 2H), 8.90 (brs, 2H),8.72 (br d, J=7.5 Hz, 1H), 8.4 4 (brs, 1H), 8.07 (brd, J=7.8 Hz, 1H),7.93 (brd, J=8.4 Hz, 2H), 7.77 (brd, J=8.4 Hz, 2H), 7.63 (brd, J=7.8 Hz,1H), 7.55 (brd, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 4.33 (brt, J=7.5Hz, 1H), 2.67 (brs, 3H), 2.36 (brs, 3H), 2.30-2.10 (m, 1H), 0.98 (brs,6H).

EXAMPLE 42(5)

2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-carboxy-2-methylpropyl)carbamoyl]benzoic acid methanesulfonanate

TLC:Rf 0.69 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ13.2-12.4 (broad, 2H), 10.86 (brs, 1H), 9.16 (brs, 2H), 8.87 (brs, 2H),8.80-8.68 (m, 2H), 8.52 (brs, 1H), 8.39 (brs, 1H), 8.05 (brd, J=7.5 Hz,1H), 7.73 (s, 4H), 7.70 (brd, J=7.5 Hz, 1H), 7.41 (brd, J=7.5 Hz, 1H),4.29 (brt, J=7.0 Hz, 1H), 2.34 (brs, 3H), 2.30-2.10 (m, 1H), 0.97 (brs,6H).

EXAMPLE 42(6)

2′-(4-amidinophenylcarbamoyl)-4-[(1-carboxy-1-methylethyl)carbamoyl]-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.51 (Ethyl acetate:Acetic acid:Water=6:2:1); NMR (d₆-DMSO): δ12.50 (br, 2H), 10.55 (s, 1H), 9.16 (s, 2H), 8.87 (s, 2H), 8.67 (s, 1H),8.30 (d, J=1.8 Hz, 1H), 7.97, (dd, J=7.8, 1.8 Hz, 1H), 7.74 (s, 4H),7.70 (dd, J=7.2, 1.2 Hz, 1H), 7.57 (dt, J=7.2, 1.2 Hz, 1H), 7.53 (dt,J=7.2, 1.2 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.27 (dd, J=7.2, 1.2 Hz,1H), 2.35 (s, 3H), 1.46 (s, 6H).

EXAMPLE 42(7)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[1(S)-(4-carboxyoxazol-2-yl)-3-methylbutyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.09 (Chloroform:Methanol:Water=7 3:0.3); NMR (d₆-DMSO): δ13.2-12.6 (broad, 2H), 10.61 (s, 1H), 9.25 (brd, J=8.0 Hz, 1H), 9.18(brs, 2H), 8.86 (brs, 2H), 8.69 (s, 1H), 8.47 (d, J=1.8 Hz, 1H), 8.07(dd, J=7.8, 1.8 Hz, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H),7.65 (d, J=8.4 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H),5.38-5.29 (m, 1H), 4.10 (s, 3H), 2.33 (s, 3H), 2.05-1.62 (m, 3H), 0.95(d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H).

EXAMPLE 43(1)-43(6)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 1, using a corresponding compound instead of acompound prepared in Reference Example 5.

EXAMPLE 43(1)

Methyl2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethylcyclopentylcarbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.42 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.63 (1H, br.s), 9.05 (3H, br.d), 8.25-8.15 (2H, m), 8.03 (1H, dd,J=8.0, 2.0 Hz), 7.74 (4H, like s), 7.69 (1H, dd, J=8.0, 2.0 Hz), 7.60(1H, dt, J=8.0, 2.0 Hz), 7.54 (1H, dt, J=8.0, 2.0 Hz), 7.40 (1H, d,J=8.0 Hz), 7.31 (1H, dd, J=8.0, 2.0 Hz), 4.09 (1H, q, J=9.0 Hz), 3.54(3H, s), 1.92 (1H, m), 1.8-1.5 (2H, m), 1.6-1.4 (3H, m), 0.98 (3H, s),0.87 (3H, s).

EXAMPLE 43(2)

Methyl2′-(4-amidinophenylcarbamoyl)-4-(3-methylbutylcarbonyl)-2-biphenylcarboxylate

TLC:Rf 0.64 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,d₆-DMSO): δ 10.67 (br.s, 1H), 9.3-8.9 (br, 3H), 8.28 (d, J=1.8 Hz, 1H),8.17 (dd, J=1.8, 7.8 Hz, 1H), 7.75 (like s, 4H), 7.71 (dd, J=1.8, 7.8Hz, 1H), 7.61 (dt, J=1.8, 7.8 Hz, 1H), 7.55 (dt, J=1.8, 7.8 Hz, 1H),7.46 (d, J=7.8 Hz, 1H), 7.32 (dd, J=1.8, 7.8 Hz, 1H), 3.54 (s, 3H), 3.05(t, J=7.0 Hz, 2H), 1.57 (like septet, J=7.0 Hz, 1H), 1.51 (q, J=7.0 Hz,2H), 0.89 (d, J=7.0 Hz, 6H).

EXAMPLE 43(3)

Methyl2′-(4-amidinophenylcarbamoyl)-4-[(N-methyl-N-t-butylamino)carbamoyl]-2-biphenylcarboxylate

TLC:Rf 0.23 (Chloroform:Methanol:Water=8:2:0.2); NMR (200 MHz, CD₃OD): δ8.25 (d, J=2.0 Hz, 1H), 7.94 (dd, J=8.0, 2.0 Hz, 1H), 7.73-7.65 (m, 5H),7.61 (dt, J=8.0, 2.0 Hz, 1H), 7.55 (dt, J=8.0, 2.0 Hz, 1H), 7.45 (d,J=8.0 Hz, 1H), 7.30 (dd, J=8.0,2.0 Hz, 1H), 3.69 (s, 3H), 2.57 (s, 3H),1.17 (s, 9H).

EXAMPLE 43(4)

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(3-methyl-2-butenyl)carbamoyl]benzoate

TLC:Rf 0.8 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,CD₃OD): δ 8.51 (d, J=1.8 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz, 1H), 7.84 (d,J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 7.54 (d, J=7.8 Hz, 1H), 7.43 (d,J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.25-7.17 (m, 3H), 7.05 (brt,J=6.3 Hz, 1H), 5.32 (brt, J=7.2 Hz, 1H), 5.00 (d, J=6.0 Hz, 2H), 4.00(d, J=7.2 Hz, 2H), 2.64 (s, 3H), 1.76 (s, 6H).

EXAMPLE 43(5)

Benzyl2′-(4-amidinophenylcarbamoyl)-5′-nitro-4-(2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylate

TLC:Rf 0.25 (Chloroform:Methanol:Water=8:2:0.2); NMR (200 MHz, CD₃OD): δ8.44 (d, J=2.0 Hz, 1H), 8.21 (dd, J=8.0, 2.0 Hz, 1H), 8.08 (d, J=2.0 Hz,1H), 8.02 (dd, J=8.0,2.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.72 (d, J=9.0Hz, 2H), 7.66 (d, J=9.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.21 (m, 3H),7.15-7.10 (m, 2H), 5.10 (s, 2H), 3.21 (s, 2H), 0.96 (s, 9H).

EXAMPLE 43(6)

Methyl3-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-6-[(1-isopropyl-2-methylpropyl)carbamoyl]-2-pyridinecarboxylate

TLC:Rf 0.28 (Chloroform:Methanol:Water=8:2:0.2); NMR (200 MHz, CD₃OD): δ8.32 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.90 (d, J=9.0 Hz, 2H),7.78 (d, J=9.0 Hz, 2H), 7.70 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H),4.17 (s, 3H), 3.74 (t, J=7.0 Hz, 1H), 3.67 (s, 3H), 2.04 (m, 2H), 0.98(d, J=6.6 Hz, 6H), 0.96 (d, J=6.6 Hz, 6H).

EXAMPLE 44(1)-44(6)

The following compounds were obtained by the same procedure as a seriesof reaction of Example 11, using a compound prepared in Example 43(1)-43 (6).

EXAMPLE 44(1)

2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethylcyclopentylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.36 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.6-11.8 (1H, br), 10.55 (1H, br.s), 9.14 (2H, br.s), 8.88 (2H, br.s),8.27 (1H, d, J=1.8 Hz), 8.19 (1H, d, J=9.0 Hz), 7.96 (1H, dd, J=1.8, 8.1Hz), 7.73 (4H, like s), 7.75-7.65 (1 H , m), 7.6-7.5 (2H, m), 7.31 (1H,d, J=8.1 Hz), 7.26 (1H, dd, J=1.8, 8.1 Hz), 4.08 (1H, like q, J=9.0 Hz),2.36 (3H, s), 1.91 (1H, m), 1.8-1.6 (2H, m), 1.6-1.4 (3H, m), 0.97 (3H,s), 0.87 (3H, s).

EXAMPLE 44(2)

2′-(4-amidinophenylcarbamoyl)-4-(3-methylbutylcarbonyl)-2-biphenylcarboxylic

TLC:Rf 0.33 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.90 (br.s, 1H), 10.59 (s, 11H), 9.13 (s, 2H), 8.81 (s, 2H), 8.34 (d,J=1.8 Hz, 1H), 8.10 (dd, J=1.8, 7.8 Hz, 1H), 7.8-7.65 (m, 5H), 7.65-7.5(m, 2H), 7.38 (d, J=7.8 Hz, 1H), 7.28 (dd, J=1.8, 7.8 Hz, 1H), 3.04 (t,J=7.0 Hz, 2H), 2.32 (s, 3H), 1.59 (like septet, J=7.0 Hz, 1H), 1.50 (q,J=7.0 Hz, 2H), 0.89 (d, J=7.0 Hz, 6H).

EXAMPLE 44(3)

2′-(4-amidinophenylcarbamoyl)-4-[(N-methyl-N-t-butylamino)carbamoyl]-2-biphenylcarboxylicacid dimethanesulfonate

TLC:Rf 0.33 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.65(s, 1H), 9.23 (s, 2H), 9.01 (s, 2H), 8.32 (d, J=2.0 Hz, 1H), 8.04 (dd,J=8.0, 2.0 Hz, 1H), 7.77 (s, 4H), 7.74 (dd, J=8.0, 2.0 Hz, 1H), 7.59(dt, J=8.0, 2.0 Hz, 1H), 7.54 (dt, J=8.0, 2.0 Hz, 1H), 7.38 (d, J=8.0Hz, 1H), 7.26 (dd, J=8.0, 2.0 Hz, 1H), 2.89 (s, 3H), 2.36 (s, 6H), 1.29(s, 9H).

EXAMPLE 44(4)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl)-5-[(3-methyl-2-butenyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.30 (Chloroform:Methanol:Acetic acid 10:2:1); NMR (d₆-DMSO): δ10.83 (s, 1H), 9.20 (S, 2H), 8.90 (s, 2H), 8.78 (t, J=5.4 Hz, 1H), 8.42(d, J=1.8 Hz, 1H), 8.02, (dd, J=8.4, 1.8 Hz, 1H), 7.92 (d, J=8.7 Hz,2H), 7.78 (d, J=8.7 Hz, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.8 Hz,1H), 7.29 (d, J=8.4 Hz, 1H), 5.25 (brt, J=5.4 Hz, 1H), 3.88 (t, J=5.4Hz, 2H), 2.67 (s, 3H), 2.33 (s, 3H), 1.69 (s, 6H).

EXAMPLE 44(5)

2′-(4-amidinophenylcarbamoyl)-5′-nitro-4-(2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.30 (Chloroform2:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 12.90(br.s, 1H), 10.84 (s, 1H), 9.15 (s, 2H), 8.78 (s, 2H), 8.59 (br.t, J=6.3Hz, 1H) 8.40 (dd, J=8.0,2.0 Hz), 8.39 (d, J=2.0 Hz, 1H), 8.10 (d, J=2.0Hz, 1H), 8.05 (dd, J=8.0,2.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.73 (s,4H), 7.43 (d, J=8.0 Hz, 1H), 3.12 (d, J=6.3 Hz, 2H), 2.33 (s, 3H), 0.91(s, 9H).

EXAMPLE 44(6)

3-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-6-[(1-isopropyl-2-imethylpropyl)carbamoyl]-2-pyridinecarboxylicacid methanesulfonate

TLC:Rf 0.30 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 12.95(br.s, 1H), 10.66 (s 1H), 9.18 (s, 2H), 8.81 (s, 2H), 8.59 (d, J=10.0Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.91 (d, J=9.0Hz, 2H), 7.77 (d, J=9.0 Hz, 2H ), 7.76 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0Hz, 1H ), 4.13 (s, 3H), 3.70 (dt, J=10.0,7.0 Hz, 1H), 2.31 (s, 3H), 1.98(m, 2H), 0.91 (d, J=6.0 Hz, 6H ), 0.89 (d, J=6.0 Hz, 6H).

REFERENCE EXAMPLE 26

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-t-butyldimethylsilyloxymethyl-2,2-dimethylpropyl)carbamoyl]benzoate

The title compound was obtained by the same procedure as a series ofreaction of Example 1, using3-[4-(1(S)-t-butyidimethylsilyloxy-2,2-dimethylpropylcarbamoyl)-2-benzyloxycarbonylphenyl]-6-methoxy-2-pyridinecarboxylicacid which was obtained by the same procedure as a series of reaction ofReference Example 5, using a compound prepared in Reference Example 25.

TLC:Rf 0.58 (Chloroform:Methanol:Acetic acid=20:2:1); NMR (300 MHz,CD₃OD): δ 8.46 (d, J=1.8 Hz, 1H), 7.98 (dd, J=8.0, 1.8 Hz, 1H), 7.83 (d,J=9.3 Hz, 2H), 7.77 (d, J=9.3 Hz, 2H), 7.56 (d, J=8.4 Hz, 1H), 7.32 (d,J=8.0 Hz, 1H), 7.28-7.16 (m, 3H), 7.12-7.06 (m, 2H), 6.99 (d, J=8.4 Hz,1H), 5.08 (brd, J=12 Hz, 1H), 4.99 (brd, J=12 Hz, 1H), 4.07 (dd, J=8.7,3.9 Hz, 1H), 3.95 (dd, J=10.5, 3.9 Hz, 1H), 3.74 (dd, J=10.5, 8.7 Hz,1H), 1.03 (s, 9H), 0.86 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).

EXAMPLE 45

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoate

A solution of a compound prepared in Reference Example 26 (2.15 g) inacetic acid (9 ml)/water (3 ml) was stirred for 16 hours at roomtemperature. The reaction mixture was concentrated. The residue waspurified by column chromatography on silica gel(Chloroform:Methanol:Water=7:3:0.3) to give the title compound (1.52 g)having the following physical data.

TLC:Rf 0.32 (Chloroform:Methanol:Acetic acid=20:2:1); NMR (300 MHz,CD₃OD): δ 8.52 (d, J=2.0 Hz, 1H), 8.04 (dd, J=8.0, 2.0 Hz, 1H), 7.83 (d,J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.32 (d,J=8.0 Hz, 1H), 7.28-7.16 (m, 3H), 7.10-7.05 (m, 2H), 6.99 (d, J=8.4 Hz,1H), 5.07 (brd, J=12 Hz, 1H), 4.98 (brd, J=12 Hz, 1H), 4.09 (dd, J=9.0,3.3 Hz, 1H), 4.06 (s, 3H), 3.90 (dd, J=10.4, 3.3 Hz, 1H), 3.65 (dd,J=10.4, 9.0 Hz, 1H), 1.02 (s, 9H).

EXAMPLE 46

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

The title compound (1.48 g) having the following physical data wasobtained by the same procedure as a series of reaction of Example 2,using a compound prepared in Example 45 (1.51 g).

TLC:Rf 0.21 (Chloroform:Methanol:Acetic acid=10:2:1) NMR (d₆-DMSO): δ13.0-12.4 (broad, 1H), 10.61 (s, 1H), 9.19 (brs, 2H), 8.88 (brs, 2H),8.41 (d, J=1.8 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 8.03 (dd, J=8.0, 1.8 Hz,1H), 7.90 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.64 (d, J=8.5 Hz,1H), 7.30 (d, J=8.0 Hz, H), 7.12 (d, J=8.0 Hz, 1H), 4.09 (s, 3H), 3.93(td, J=9.0, 3.5 Hz, 1H), 3.67 (dd, J=10.8, 3.5 Hz, 1H), 3.50 (dd,J=10.8, 9.0 Hz, 1H), 2.33 (s, 3H), 0.92 (s, 9H).

EXAMPLE 47(1)-47(32)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 26 Example 45 Example 46, using acorresponding compound.

EXAMPLE 47(1)

2′-[(2-amidino-5-pyridyl)carbamoyl]-4′-methoxy-4-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.42 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO+2 drops ofCD₃OD): δ 10.89 (s, 1H), 9.38 (s, 2H), 9.07 (s, 2H), 8.93 (d, J=2.0 Hz,1H), 8.30-8.28 (m, 2H), 8.20 (d, J=8.0 Hz, 1H), 8.07 (d, J=9.6 Hz, 1H),7.98 (dd, J=8.0, 2.0 Hz, 1H), 7.33-7.30 (m, 2H), 7.24 (d, J=8.0 Hz, 1H),7.17 (dd, J=8.0, 2.0 Hz, 1H), 3.90 (s, 3H), 3.67 (dd, J=11.4, 3.0 Hz,1H), 3.48 (dd, J=11.4, 9.3 Hz, 1H), 2.35 (s, 3H), 0.91 (s, 9H).

EXAMPLE 47(2)

2′-[(2-amidino-5-pyridyl)carbamoyl]-4-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.11 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.9 (s, 1H), 9.37 (br s, 2H), 9.07-9.05 (m, 2H), 8.91 (d, J=2.6 Hz,1H), 8.28 (dd, J'6.6,2.6 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.08 (d, J=9.4Hz, 1H), 8.00 (dd, J=8.0, 1.8 Hz, 1H), 7.77-7.72 (m, 1H), 7.64-7.51 (m,2H), 7.33 (d, J=8.0 Hz, 1H), 7.31-7.28 (m, 1H), 3.90-3.85 (m, 1H),3.80-3.40 (m, 2H), 3.50-3.40 (m, 1H), 2.31 (s, 3H), 0.90 (s, 9H).

EXAMPLE 47(3)

2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.18 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 11.05(s, 1H), 9.22 (brs, 2H), 8.99 (brs, 2H), 8.90 (d, J=5.5 Hz, 1H), 8.72(s, 1H), 8.41 (d, J=1.5 Hz, 1H), 8.17 (d, J=9.5 Hz, 1H), 8.07 (dd,J=8.0, 1.5 Hz, 1H), 7.93 (d, J=5.5 Hz, 1H), 7.76 (like s, 4H), 7.46 (d,J=8.0 Hz, 1H), 3.90 (td, J=9.5, 3.5 Hz, 1H), 3.66 (dd, J=11.0, 3.5 Hz,1H), 3.47 (dd, J=11.0, 9.5 Hz, 1H), 2.36 (s, 3H), 0.90 (s, 9H).

EXAMPLE 47(4)

2-[4-[(2-amidino-5-pyridyl)carbamoyl]-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.18 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 11.38(s, 1H), 9.44 (brs, 2H), 9.23 (brs, 2H), 8.94 (d, J=2.0 Hz, 1H), 8.90(d, J=5.0 Hz, 1H), 8.70 (s, 1H), 8.40 (d, J=1.5 Hz, 1H), 8.29 (dd,J=9.0, 2.0 Hz, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.08(dd, J=8.0,1.5 Hz, 1H), 7.93 (d, J=5.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H),3.90 (td, J=9.0, 3.5 Hz, 1H), 3.66 (dd, J=11.0, 3.5 Hz, 1H), 3.47 (dd,J=11.0, 9.0 Hz, 1H), 2.36 (s, 3H), 0.90 (s, 9H).

EXAMPLE 47(5)

2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.30 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ11.00 (s, 1H), 9.20 (s, 2H), 8.94 (s, 2H), 8.73 (dd, J=4.5, 2.1 Hz, 1H),8.43 (d, J=2.1 Hz, 1H), 8.15 (br.d, J=9.0 Hz, 1H), 8.08 (dd, J=8.1, 2.1Hz, 1H), 7.95 (d, J=9.0 Hz, 2H), 7.8-7.65 (m, 4H), 733 (d, J=8.1 Hz,1H), 5.4-4.6 (br, 2H), 3.94 (td, J=9.0, 3.6 Hz, 1H), 3.68 (dd, J=11.1,3.6 Hz, 1H), 3.51 (dd, J=11.1, 9.0 Hz, 1H), 2.37 (s, 3H), 0.93 (s, 9H).

EXAMPLE 47(6)

2-[2-[(2-amidino-5-pyridyl)carbamoyl]-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.26 (Chloroform:Methanol:Acetic acid 10:2:1); NMR (d₆-DMSO): δ13.0-12.4 (br, 1H), 11.34 (s, 1H), 9.40 (br.s, 2H), 9.12 (d, J=2.0 Hz,1H), 9.09 (br.s, 2H), 8.76 (dd, J=4.2, 2.1 Hz, 1H), 8.49 (dd, J=9.0, 2.0Hz, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.20 (d, J=9.0 Hz, 1H), 8.15 (br.d,J=9.3 Hz, 1H), 8.09 (dd, J=8.0, 2.0 Hz, 1H), 7.8-7.7 (m, 2H), 7.35 (d,J=8.0 Hz, 1H), 3.94 (td, J=9.3, 3.3 Hz, 1H), 3.9-3.7 (br, 1H), 3.69 (dd,J=10.8, 3.3 Hz, 1H), 3.50 (dd, J=10.8,9.3 Hz, 1H), 2.31 (s, 3H), 0.93(s, 9H).

EXAMPLE 47 (7)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.09 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.85 (s, 1H), 9.21 (brs, 2H), 8.94 (brs, 2H), 8.42 (d, J=1.8 Hz, 1H),8.14 (d, J=9.3 Hz, 1H), 8.05 (dd, J=8.0, 1.8 Hz, 1H), 7.93 (d, J=9.0 Hz,2H), 7.78 (d, J=9.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz,1H), 7.30 (d, J=8.0 Hz, 1H), 3.93 (td, J=9.3, 3.5 Hz, 1H), 3.68 (dd,J=11.0, 3.5 Hz, 1H), 3.50 (dd, J=11.0, 9.3 Hz, 1H), 2.67 (s, 3H), 2.36(s, 3H), 0.93 (s, 9H).

EXAMPLE 47(8)

2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1(S)-hydroxymethyl-3-methylbutyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.23 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.8 (s, 1H), 9.21 (br s, 2H), 8.93 (br s, 2H), 8.42 (d, J=1.8 Hz, 1H),8.27 (d, J=8.7 Hz, 1H), 8.05 (dd, J=8.1,1.8 Hz, 1H), 7.93 (d, J=8.1 Hz,2H), 7.78 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.1 Hz, 1H), 7.55 (d, J=8.1 Hz,1H), 7.29 (d, J=8.1 Hz, 1H) 4.20-4.10 (m, 1H), 3.47-3.33 (m, 2H), 2.67(s, 3H), 2.36 (s, 3H), 1.70-1.30 (m, 3H), 0.91-0.87 (m, 6H).

EXAMPLE 47(9)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-4-methyl-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.37 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.59(s, 1H), 9.21 (s, 2H), 8.89 (s, 2H), 8.07 (d, J=9.0 Hz, 1H), 7.91 (d,J=9.0 Hz, 2H), 7.89 (s, 1H), 7.79 (d, J=9.0 Hz, 2H), 7.58 (d, J=8.0 Hz,1H), 7.10 (d, J=8.0 Hz, 1H), 7.08 (s, 1H), 4.09 (s, 3H), 3.40 (t, J=9.0Hz, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 0.94 (s, 9H).

EXAMPLE 47(10)

2-[3-(4-amidinophenylcarbamoyl)-2-thienyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.31 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.32(s, 1H), 9.18 (s, 2H), 8.89 (s, 2H), 8.30 (d, J=2.0 Hz, 1H), 8.13 (br.d,J=9.3 Hz, 1H), 8.01 (dd, J=8.0,2.0 Hz, 1H), 7.83 (d, J=9.0 Hz, 2H), 7.75(d, J=9.0 Hz, 2H), 7.72 (d, J=5.6 Hz, 1H), 7.65 (d, J=5.6 Hz, 1H), 7.48(d, J=8.0 Hz, 1H), 3.90 (m, 1H), 3.67 (dd, J=11.5,3.3 Hz, 1H), 3.48 (dd,J=11.5,9.0 Hz, 1H), 2.33 (s, 3H), 0.91 (s, 9H).

EXAMPLE 47(11)

2-[2-(4-amidinophenylcarbamoyl)-3-thienyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyllbenzoicacid methanesulfonate

TLC:Rf 0.35 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.4 (br, 1H), 10.18 (s, 1H ), 9.18 (s, 2H), 8.87 (s, 2H), 8.30 (d,J=1.8 Hz, 1H), 8.09 (br.d, J=9.6 Hz, 1H), 8.02 (dd, J=8.0, 1.8 Hz, 1H),7.84 (d, J=5.0 Hz, 1H), 7.74 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H),7.41 (d, J=8.0 Hz, 1H), 7.11 (d, J=5.0 Hz, 1H), 3.91 (m, 1H), 3.66 (m,1H), 3.65-3.45 (br, 1H), 3.48 (m, 1H), 2.32 (s, 3H), 0.91 (s, 9H).

EXAMPLE 47(12)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1-hydroxymethyl-1-methoxycarbonyl-3-methylbutyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.54 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 12.75(br.s, 1H), 10.61 (s, 1H), 9.19 (s, 2H), 8.86 (s, 2H), 8.38 (d, J=2.0Hz, 1H), 8.25 (s, 1H), 8.00 (dd, J=8.0,2.0 Hz, 1H), 7.90 (d, J=9.0 Hz,2H), 7.78 (d, J=9.0 Hz, 2H), 7.65 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz,1H), 7.13 (d, J=8.0 Hz, 1H), 4.10 (s, 3H), 3.82 (s, 2H), 3.62 (s, 3H),2.31 (s, 3H), 1.96 (dd, J=13.6,6.3 Hz, 1H), 1.87 (dd, J=13.6,6.3 Hz,1H), 1.65 (m, 1H), 0.87 (d, J=5.7 Hz, 3H), 0.85 (d, J=5.7 Hz, 3H).

EXAMPLE 47(13)

2-[2-(N-(4-amidinophenyl)-N-methylcarbamoyl]-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzeicacid methanesulfonate

TLC:Rf 0.35 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (CD₃OD): δ8.48 (d, J=2.0 Hz, 1H), 8.01 (dd, J=8.2,2.0 Hz, 1H), 7.67 (d, J=8.4 Hz,2H), 7.54 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz,2H), 6.82 (d, J=8.4 Hz, 1H), 4.09 (dd, J=9.0, 3.6 Hz, 1H), 3.90 (dd,J=11.6, 3.6 Hz, 1H), 3.83 (s, 3H), 3.43 (dd, J=11.6, 9.0 Hz, 1H), 3.28(s, 3H), 2.70 (s, 3H), 1.02 (s, 9H).

EXAMPLE 47(14)

2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.38 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.19 (br s, 2H), 8.87 (br s, 2H), 8.40 (d, J=1.5 Hz, 1H),8.11 (d, J=9.3 Hz, 1H), 8.03 (dd, J=8.1, 1.5 Hz, 1H), 7.89 (d, J=9.0 Hz,2H), 7.77 (d, J=9.0 Hz, 2H), 7.63 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.1 Hz,1H), 7.10 (d, J=8.7 Hz, 1H), 4.56 (q, J=6.9 Hz, 2H), 3.93 (dt, J=3.9,9.3 Hz, 1H), 3.68 (dd, J=11.1, 3.9 Hz, 1H), 3.53-3.34 (m, 1H), 2.31 (s,3H), 1.41 (t, J=6.9 Hz, 3H), 0.92 (s, 9H).

EXAMPLE 47(15)

2-[2-(4-amidinophenylcarbamoyl)-6-isopropyloxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.50 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.5 (s, 1H), 9.19 (br s, 2H), 8.85 (br s, 2H), 8.40 (d, J=2.1 Hz, 1H),8.11 (d, J=9.6 Hz, 1H), 8.03 (dd, J=8.1, 2.1 Hz, 1H), 7.88 (d, J=8.7 Hz,2H), 7.77 (d, J=8.7 Hz, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.1 Hz,1H), 7.04 (d, J=8.4 Hz, 1H), 5.59 (quintet, J=6.0 Hz, 1H), 3.93 (dt,J=3.9, 9.0 Hz, 1H), 3.68 (dd, J=11.1, 3.9 Hz, 1H), 3.53-3.34 (m, 1H),2.31 (s, 3H), 1.38 (d, J=6.0 Hz, 6H), 0.92 (s, 9H).

EXAMPLE 47 (16)

2-(2-(4-amidinophenylcarbamoyl)-6-chloro-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.40 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.86 (s, 1H), 9.19 (s, 2H), 8.89 (s, 2H), 8.43 (d, J=1.2 Hz, 1H), 8.15(d, J=9.0 Hz, 1H), 8.07 (dd, J=8.1, 1.2 Hz, 1H), 7.89 (d, J=8.7 Hz, 2H),7.84 (d, J=8.7 Hz, 1H), 7.80 (J=8.7 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H),7.35 (d, J=8.1 Hz, 1H), 3.93 (dt, J=3.3, 9.0 Hz, 1H), 3.67 (dd, J=11.4,3.3 Hz, 1H), 3.45 (m, 1H), 2.32 (s, 3H), 0.92 (s, 9H).

EXAMPLE 47(17)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-(2-hydroxyethyl)-2,2-dimethylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.71 (Chloroform:Ethyl acetate:Water=3:1:1); NMR (d₆-DMSO): δ12.70 (brs, 1H), 10.62 (s, 1H), 9.18 (s, 2H), 8.79 (s, 2H), 8.40 (d,J=1.8 Hz, 1H), 8.13 (d, J=9.3 Hz, 2H), 8.02 (dd, J=7.8,1.8 Hz, 1H), 7.92(d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.65 (d, J=8.1 Hz, 1H), 7.30(d, J=7.8 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 4.35 (m, 1H), 4.11 (s, 3H),3.94 (t, J=10.8 Hz, 1H), 3.42 (t, J=9.9 Hz, 1H), 2.31 (s, 3H), 1.74 (m,1H), 1.65 (m, 1H), 0.93 (s, 9H).

EXAMPLE 47(18)

3-[3-(4-amidinophenylcarbamoyl)-2-thienyl]-6-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-pyridinecarboxylic acid methanesulfonate

TLC Rf 0.31 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.45(s 1H), 9.20 (s, 2H), 8.93 (s, 2H), 8.50 (d, J=10.2 Hz, 1H), 8.21 (d,J=8.0 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.86 (d, J=9.0 Hz, 2H), 7.82 (d,J=5.7 Hz, 1H ), 7.77 (d, J=9.0 Hz, 2H ), 7.76 (d, J=5.7 Hz, 1H ), 3.89(m, 1H), 3.71 (dd, J=11.4,3.3 Hz, 1H), 3.55 (dd, J=11.4,8.0 Hz, 1H),2.35 (s, 3H), 0.94 (s, 9H).

EXAMPLE 47(19)

3-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-6-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-pyridinecarboxylicacid methanesulfonate

TLC:Rf 0.33 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 12.95(br.s, 1H), 10.66 (s 1H), 9.21 (s, 2H), 8.91 (s, 2H), 8.67 (d, J=10.0Hz, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.91 (d, J=9.0Hz, 2H), 7.79 (d, J=9.0 Hz, 2H ), 7.76 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0Hz, 1H ), 4.12 (s, 3H), 3.93 (m, 1H), 3.74 (dd, J=11.0,3.6 Hz, 1H), 3.56(dd, J=11.0,8.7 Hz, 1H), 2.33 (s, 3H), 0.95 (s, 9H).

EXAMPLE 47(20)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[1(S)-(2-hydroxyethylcarbamoyl)-3-methylbutyl]carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.16 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 12.71(br, 1H), 10.60 (s, 1H), 9.25 (s, 2H), 9.01 (s, 2H), 8.70 (d, J=5.4 Hz,1H), 8.45 (d, J=2.1 Hz, 1H), 8.08 (dd, J=8.1, 2.1 Hz, 1H), 7.97 (t,J=5.7 Hz, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 7.63 (d,J=8.4 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 4.53 (m,1H), 3.44-3.20 (m, 2H), 3.18-3.04 (m, 2H), 2.33 (s, 3H), 1.75-1.62 (m,2H), 1.51 (m, 1H), 0.89 (d, J=6.3 Hz, 3H), 0.87 (d, J=6.0 Hz, 3H).

EXAMPLE 47(21)

3-[2-(2-amidino-5-pyridylcarbamoyl)-6-methoxy-3-pyridyl]-6-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-pyridinecarboxylic acidmethanesulfonate

TLC:Rf 0.22 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 12.95(br.s, 1H), 10.92 (s 1H), 9.40 (s, 2H), 9.14 (s, 2H), 9.05 (d, J=2.0 Hz,1H), 8.66 (d, J=10.0 Hz, 1H), 8.42 (dd, J=9.0,2.0 Hz, 1H), 8.27 (d,J=8.0 Hz, 1H), 8.22 (d, J=9.0 Hz, 1 H ), 7.96 (d, J=8.0 Hz, 1H), 7.78(br.d, J=8.4 Hz, 1H ), 7.22 (d, J=8.4 Hz, 1H), 4.13 (s, 3H, 3.92 (m,1H), 3.76 (m, 1H), 3.56 (m, 1H), 2.32 (s, 3H), 0.95 (s, 9H).

EXAMPLE 47(22)

2-[2-(4-amidinophenylcarbamoyl)-6-dimethylamino-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoic acid dimethanesulfonate

TLC:Rf 0.21 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.17 (br s, 2H), 8.82 (br s, 2H), 8.35 (d, J=2.1 Hz, 1H),8.07 (d, J=9.6 Hz, 1H), 7.99 (dd, J=8.1, 2.1 Hz, 1H), 7.89 (d, J=9.0 Hz,2H), 7.76 (d, J=9.0 Hz, 2H), 7.40 (d, J=8.7 Hz, 1H), 7.25 (d, J=8.1 Hz,1H), 6.93 (d, J=8.7 Hz, 1H), 3.92 (dt, J=3.6, 9.0 Hz, 1H), 3.88-3.54 (m,1H), 3.49 (dd, J=10.5, 9.0 Hz, 1H), 3.17 (s, 6H), 2.33 (s, 6H), 0.92 (s,9H).

EXAMPLE 47(23)

2-[2-(4-amidinophenoxycarbonyl)-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.13 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.01 (brs, 1H), 9.30 (brs, 2H), 8.99 (brs, 2H), 8.40 (d, J=1.8 Hz, 1H),8.12 (brd, J=9.3 Hz, 1H), 8.08 (brd, J=8.0 Hz, 1H), 7.80 (d, J=8.7 Hz,2H), 7.74 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.4 Hz,1H), 7.19 (d, J=8.7 Hz, 2H), 4.60-4.30 (broad, 1H), 3.99 (s, 3H), 3.90(dt, J=3.3, 9.3 Hz, 1H), 3.66 (dd, J=10.8, 3.3 Hz, 1H), 3.47 (dd,J=10.8, 9.3 Hz, 1H), 2.30 (s, 3H), 0.90 (s, 9H).

EXAMPLE 47(24)

2-[2-(4-amidinophenylcarbamoyl)-6-butoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.29 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.18 (br s, 2H), 8.82 (br s, 2H), 8.40 (d, J=1.8 Hz, 1H),8.11 (d, J=6.3 Hz, 1H), 8.03 (dd, J=8.1, 6.3 Hz, 1H), 7.89 (d, J=9.0 Hz,2H), 7.77 (d, J=9.0 Hz, 2H), 7.63 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.1 Hz,1H), 7.10 (d, J=8.4 Hz, 1H), 4.51 (t, J=6.6 Hz, 2H), 3.93 (dt, J=3.3,9.0 Hz, 1H), 3.68 (dd, J=3.3, 8.1 Hz, 1H), 3.53-3.34 (m, 1H), 2.30 (s,3H), 1.78 (quintet, J=6.6 Hz, 2H), 1.49 (sextet, J=6.6 Hz, 2H), 0.97 (t,J=6.6 Hz, 3H), 0.92 (s, 9H).

EXAMPLE 47(25)

2-[2-(2-amidinopyrimidin-5-yl)carbamoyl-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoic acid methanesulfonate

TLC:Rf 0.24 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ13.0-12.4 (br, 1H), 11.05 (s, 1H), 9.59 (s, 2H), 9.35 (s, 2H), 9.32 (s,2H), 8.41 (d, J=1.5 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 8.06 (dd, J=8.4 Hz,1H), Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.18 (d,J=8.4 Hz, 1H), 4.11 (s, 3H), 3.93 (dt, J=3.3, 9.0 Hz, 1H), 3.75-3.60 (m,1H), 3.65-3.30 (m, 2H), 2.30 (s, 3H), 0.92 (s, 9H).

EXAMPLE 47(26)

2-[2-(4-amidinophenylcarbamoyl)-6-propoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.20 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.19 (br s, 2H), 8.86 (br s, 2H), 8.40 (d, J=1.5 Hz, 1H),8.11 (d, J=9.3 Hz, 1H), 8.03 (dd, J=8.1, 1.5 Hz, 1H), 7.89 (d, J=9.0 Hz,2H), 7.77 (d, J=9.0 Hz, 2H), 7.63 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.1 Hz,1H), 7.10 (d, J=8.7 Hz, 1H), 4.46 (t, J=6.6 Hz, 2H), 3.93 (dt, J=3.3,9.3 Hz, 1H), 3.68 (dd, J=11.1, 3.3 Hz, 1H), 3.51 (dd, J=11.1, 9.3 Hz,1H), 2.31 (s, 3H), 1.81 (sextet, J=6.6 Hz, 2H), 1.04 (t, J=6.6 Hz, 3H),0.92 (s, 9H).

EXAMPLE 47(27)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S),2-bishydroxy methyl-2-methylpropyl)carbamoyl]benzoic acidmethanesulfonate

TLC:Rf 0.60 (Ethyl acetate:Acetic acid:Water=3:1:0.5); NMR (d₆-DMSO): δ12.71 (br.s, 1H), 10.61 (s, 1H), 9.18 (s, 2H), 8.82 (s, 2H), 8.41 (d,J=1.8 Hz, 1H), 8.23 (d, J=8.7 Hz, 1H), 8.03 (dd, J=8.1, 1.8 Hz, 1H),7.90 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.65 (d, J=8.7 Hz, 1H),7.31 (d, J=8.1 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 4.10 (s, 3H), 4.01 (m,1H), 3.70 (dd, J=10.8, 3.3 Hz, 1H), 3.57 (dd, J=10.8, 9.0 Hz, 1H),3.80-3.20 (br, 2H), 3.27 (d, J=10.8 Hz, 1H), 3.11 (d, J=10.8 Hz, 1H),2.31 (s, 3H), 0.92 (s, 3H), 0.83 (s, 3H).

EXAMPLE 47(28)

2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S),2-bishydroxy methyl-2-methylpropyl)carbamoyl]benzoic acidmethanesulfonate

TLC:Rf 0.60 (Ethyl acetate:Acetic acid:Water=3:1:0.5); NMR (d₆-DMSO): δ12.72 (br, 1H), 10.57 (s, 1H), 9.19 (s, 2H), 8.84 (s, 2H), 8.40 (d,J=1.8 Hz, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.02 (dd, J=8.1, 1.8 Hz, 1H),7.89 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.64 (d, J=8.4 Hz, 1H),7.31 (d, J=8.1 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 4.56 (q, J=6.9 Hz, 2H),4.01 (d, J=3.6, 9.0 Hz, 1H), 3.69 (dd, J=11.0, 3.6 Hz, 1H), 3.57 (dd,J=11.0, 9.0 Hz, 1H), 3.80-3.20 (br, 2H), 3.27 (d, J=11.0 Hz, 1H), 3.11(d, J=11.0 Hz, 1H), 2.30 (s, 3H), 1.41 (t, J=6.9 Hz, 3H), 0.92 (s, 3H),0.82 (s, 3H).

EXAMPLE 47(29)

5-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-2-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-4-pyridinecarboxylicacid methanesulfonate

TLC:Rf 0.26 (Chloroform:Methanol:Water=7:3:0.3); NMR (300 MHz, DMSO-d₆):δ 13.47 (br.s, 1H), 10.66 (s 1H), 9.24 (s, 2H), 8.99 (s, 2H), 8.58 (s,1H), 8.41 (s, 1H), 8.32 (d, J=10.0 Hz, 1H), 7.91 (d, J=9.0 Hz, 2H),7.81-7.78 (m, 3H), 7.20 (d, J=8.8 Hz, 1H), 4.12 (s, 3H), 3.86 (m, 1H),3.63-3.60 (m, 2H), 2.32 (s, 3H), 0.94 (s, 9H).

EXAMPLE 47(30)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2-methylpropyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.09 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,d₆-DMSO): δ 12.8-12.5 (broad, 1H), 10.61 (s, 1H), 9.17 (brs, 2H), 8.81(brs, 2H), 8.42 (d, J=2.0 Hz, 1H), 8.21 (brd, J=9.0 Hz, 1H), 8.04 (dd,J=8.0, 2.0 Hz, 1H), 7.90 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.65(d, 8.4 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.09(s, 3), 3.90-3.80 (m, 1H), 3.58-3.47 (m, 2H), 2.32 (s, 3H), 1.99-1.87(m, 1H), 0.92 (d, J=6.9 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H).

EXAMPLE 47(31)

2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-3,3-dimethylbutyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.35 (Chloroform:Methanol:Water=7:3:0.3); NMR (300 MHz, DMSO-d₆):δ 12.68 (br.s, 1H), 10.57 (s 1H), 9.19 (s, 2H), 8.85 (s, 2H), 8.39 (d,J=2.0 Hz, 1H), 8.28 (br.d, J=9.0 Hz, 1H), 8.00 (dd, J=8.0,2.0 Hz, 1H),7.89 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 1H),7.28 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 4.55 (q, J=7.0 Hz, 2H),4.12 (m, 1H), 3.41-3.22 (m, 3H), 2.31 (s, 3H), 1.52 (d, J=5.4 Hz, 2H),1.41 (t, J=7.0 Hz, 3H), 0.91 (s, 9H).

EXAMPLE 47(32)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-3,3-dimethylbutyl)carbamoyl]benzoicacid methanesulfonate

TLC:Rf 0.50 (Chloroform:Methanol:Water=7:3:0.3); NMR (300 MHz, DMSO-d₆):δ 12.68 (br.s, 1H), 10.57 (s 1H), 9.19 (s, 2H), 8.85 (s, 2H), 8.39 (d,J=2.0 Hz, 1H), 8.28 (br.d, J=9.0 Hz, 1H), 8.00 (dd, J=8.0,2.0 Hz, 1H),7.89 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 1H),7.28 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 4.55 (q, J=7.0 Hz, 2H),4.12 (m, 1H), 3.41-3.22 (m, 3H), 2.31 (s, 3H), 1.52 (d, J=5.4 Hz, 2H),1.41 (t, J=7.0 Hz, 3H), 0.91 (s, 9H).

EXAMPLE 48(1)-48(3)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 26→Example 45→Example 11, using acorresponding compound.

EXAMPLE 48(1)

2′-(4-amidinophenylcarbamoyl)-4′-hydroxymethyl-4-(2-methylpropylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.50 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 10.53(s, 1H), 9.13 (s, 2H), 8.75 (s, 2H), 8.64 (br.t, J=6.3 Hz, 1H), 8.30 (d,J=2.0 Hz, 1H), 7.95 (dd, J=8.0, 2.0 Hz, 1H), 7.72 (s, 4H), 7.62 (s, 1H),7.51 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H),4.65 (s, 2H), 3.09 (t, J=6.3 Hz, 2H), 2.32 (s, 3H), 1.85 (m, 1H), 0.89(d, J=6.6 Hz, 6H).

EXAMPLE 48(2)

2′-(4-amidinophenylcarbamoyl)-4′-hydroxymethyl-4-(1,2,2-trimethylpropylcarbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.18 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 10.57(s, 1H), 9.13 (s, 2H), 8.79 (s, 2H), 8.26 (d, J=2.0 Hz, 1H), 8.17 (d,J=6.3 Hz, 1H), 7.93 (dd, J=8.0,2.0 Hz, 1H), 7.73 (s, 4H), 7.63 (s, 1H),7.51 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H),5.42 (br.s, 1H), 4.65 (s, 2H), 3.99 (m, 1H), 2.33 (s, 3H), 1.08 (d,J=6.6 Hz 3H), 0.90 (s, 9H).

EXAMPLE 48(3)

3-[2-(4-amidinophenylcarbamoyl)-4-methoxyphenyl]-6-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-pyridinecarboxylicacid methanesulfonate

TLC:Rf 0.27 (Chloroform:Methanol:Water=8:2:0.2); NMR (d₆-DMSO): δ 13.04(br.s, 1H), 10.82 (br.s 1H), 9.14 (s, 2H), 8.81 (s, 2H), 8.48 (br.d,J=10.2 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.75 (s,4H), 7.33-7.17 (m, 3H), 4.62 (br.s, 1H), 3.90 (s, 3H), 3.85-3.40 (m,3H), 2.31 (s, 3H), 0.92 (s, 9H).

REFERENCE EXAMPLE 27

4-[(2-trifluoromethylsulfonyloxyphenyl)carbonylamino]phenylnitrile

Trifluoromethanesulfonic acid anhydrous (0.75 ml) was dropped into asolution of 2-(4-cyanophenylcarbamoyl)phenol (895 mg) in pyridine (5 ml)at 0° C. The mixture was stirred for 1 hour at 0° C. The reactionmixture was diluted with water, and extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1→1:1) to give the present compound (1.25 g)having the following physical data.

TLC:Rf 0.20 (Hexane:Ethyl acetate=2:1); NMR (200 MHz, CDCl₃): δ 8.09(br.s, 1H), 7.92 (dd, J=8.0, 1.5 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.67(d, J=8.8 Hz, 2H), 7.70-7.60 (m, 1H), 7.56 (dt, J=1.5, 8.0 Hz, 1H), 7.42(dd, J=8.0, 1.5 Hz, 1H).

EXAMPLE 49

Ethyl 2-[2-(4-amidinophenylcarbamoyl)phenyl]-5-(2,2-dimethylpropylcarbamoyl)-3-furancarboxylate

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 37, using4-[2-[5-(2,2-dimethylpropylcarbamoyl)-3-ethoxycarbonyl-2-furyl]phenylcarbonylamino]phenylmethylthioimidatelwhich was obtained by the same procedure as a series of reaction ofReference Example 4→Reference Example 8→Reference Example 5→ReferenceExample 3→Reference Example 20, using a compound prepared in ReferenceExample 27.

TLC:Rf 0.63 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (300 MHz,d₆-DMSO): δ 11.0-10.4 (br, 1H), 10.4-9.6 (br, 3H), 8.19 (t, J=6.6 Hz,1H), 7.85-7.75 (m, 2H), 7.75 (like s, 4H), 7.7-7.65 (m, 2H), 7.51 (s,1H), 4.06 (q, J=7.0 Hz, 2H), 2.99 (d, J=6.6 Hz, 2H), 1.10 (t, J=7.0 Hz,3H), 0.82 (s, 9H).

EXAMPLE 50

2-[2-(4-amidinophenylcarbamoyl)phenyl]-5-(2,2-dimethylpropylcarbamoyl)-3-furancarboxylicacid methanesulfonate

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 11, using acompound prepared in Example 49.

TLC:Rf 0.31 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.9-12.6 (br, 1H), 10.80 (s, 1H), 9.17 (s, 2H), 8.85 (s, 2H), 8.15 (t,J=6.6 Hz, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.8-7.7(m, 2H), 7.7-7.6 (m, 2H), 7.45 (s, 1H), 2.99 (d, J=6.6 Hz, 2H), 2.33 (s,3H), 0.81 (s, 9H).

EXAMPLE 51

Benzyl2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(3-amino-1(S)-t-butylpropyl)carbamoyl]benzoatedihydrochloride

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 1→ReferenceExample 8, using304-(3-t-butylcarbonylamino-1(R)-t-butylpropylcarbamoyl)-2-benzyloxycarbonylphenyl]-6-methoxy-2-pyridinecarboxylicacid which was prepared by the same procedure as a series of reaction ofReference Example 1→Reference Example 2→Reference Example 3→ReferenceExample 4→Reference Example 5 using a corresponding compound.

TLC:Rf 0.10 (Chloroform:Methanol:Acetic acid=10:2:1)).

EXAMPLE 52

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(3-amino-1(S)-t-butylpropyl)carbamoyl]benzoicacid dimethanesulfonate

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 2, using acompound prepared in Example 51.

TLC:Rf 0.60 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ12.75 (br, 1H), 10.63 (s, 1H), 9.19 (s, 2H), 8.84 (s, 2H), 8.41 (d,J=1.8 Hz, 1H), 8.28 (d, J=9.9 Hz, 1H), 8.04 (dd, J=8.1, 1.8 Hz, 1H),7.92 (d, J=9.3 Hz, 2H), 7.79 (d, J=9.3 Hz, 2H), 7.71 (br, 2H), 7.64 (d,J=8.7 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 4.11 (s,3H), 3.96 (m, 1H), 2.85-2.70 (m, 2H), 2.32 (s, 6H), 1.91 (m, 1H), 1.77(m, 1H), 0.96 (s, 9H).

EXAMPLE 53(1)-53(8)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 8→Example 52 (without a procedure ofconversion to methanesulfoxide thereof, using a compound prepared inExample 40(51), or were obtained by the same procedure as a series ofreaction of Example 51→Example 52 using a corresponding compound.

EXAMPLE 53(1)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1,1-bishydroxymethyl-2-methylpropyl)carbamoyl]benzoic acid hydrochloride

TLC:Rf 0.50 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.0-11.4 (br, 1H), 9.23 (s, 2H), 9.11 (s, 2H), 8.18 (s, 1H), 7.84-7.71(m, 6H), 7.61 (s, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H),7.03 (d, J=8.4 Hz, 1H), 4.94 (d, J=5.4 Hz, 1H), 4.92 (d, J=5.4 Hz, 1H),3H), 3.74 (dd, J=11.4, 5.4 Hz, 2H), 3.65 (dd, J=11.4, 5.4 Hz, 2H), 2.41(m, 1H), 0.93 (d, J=6.9 Hz, 6H).

EXAMPLE 53(2)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-amino-2-hydroxymethyl-3-methylbutyl)carbamoyl]benzoicacid hydrochloride

TLC:Rf 0.20 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.9-12.5 (br, 1H), 9.36 (s, 2H), 9.26 (s, 2H), 8.60-7.90 (br, 2H), 8.28(s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.77 (d, J=8,7 Hz, 2H), 7.68 (d, J=8.7Hz, 2H), 7.49 (d, J=8.4 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 5.55 (br, 1H), 4.37 (s, 2H), 3.97 (s, 3H), 3.64 (s, 2H), 2.18(dd, J=7.2, 6.6 Hz, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H).

EXAMPLE 53(3)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(4-(2-methylpropyl)-4-piperidino)carbamoyl]benzoicacid dimethanesulfonate

TLC:Rf 0.70 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.6 (s, 1H), 9.19 (br s, 2H), 8.89 (br s, 2H), 8.43 (br s, 2H), 8.36(d, J=2.1 Hz, 1H), 8.06 (s, 1H), 8.02 (dd, J=8.1, 2.1 Hz, 1H), 7.90 (d,J=9.3 Hz, 2H), 7.79 (d, J=9.3 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.30 (d,J=8.7 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 4.10 (s, 3H), 3.20-3.16 (m, 2H),3.06-3.02 (m, 2H), 2.64-2.59 (m, 2H), 2.33 (s, 6H), 1.80-1.55 (m, 1H),1.7 4 (s, 2H), 1.66-1.59 (m, 2H), 0.90 (d, J=6.0 Hz, 6H).

EXAMPLE 53(4)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-amino-3-methylbutyl)carbamoyl]benzoic acid methanesulfonate trifluoroacetate

TLC:Rf 0.50 (Ethyl acetate:Acetic acid:Water=3:3:1); NMR (d₆-DMSO): δ12.8-12.5 (br, 1H), 10.61 (s, 1H), 9.21 (s, 2H), 9.02 (s, 2H), 8.84 (t,J=5.7 Hz, 1H), 8.44 (d, J=1.8 Hz, 1H), 8.07 (dd, J=8.1, 1.8 Hz, 1H),7.93 (brd, J=3.6 Hz, 2H), 7.91 (d, J=9.0 Hz, 2H), 7.79 (d, J=9.0 Hz,2H), 7.64 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.12 (d, J=8.4 Hz,1H), 4.10 (s, 3H), 3.5-3.3 (m, 3H), 3.08 (m, 1H), 2.34 (s, 3H), 1.96 (m,1H), 1.01 (d, J=6.6 Hz, 3H), 0.99 (d J=6.6 Hz, 3H).

EXAMPLE 53(5)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-(4-aminobutylcarbamoyl)-3-methylbutyl)carbamoyl]benzoic acid dimethanesulfonate

TLC:Rf 0.66 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ12.75 (br, 1H), 10.62 (s, 1H), 9.21 (s, 2H), 8.89 (s, 2H), 8.70 (d,J=8.4 Hz, 1H), 8.47 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.1, 1.8 Hz, 1H),8.06 (t, J=5.7 Hz, 1H), 7.91 (d, J=9.3 Hz, 2H), 7.80 (d, J=9.3 Hz, 2H),7.72 (br, 2H), 7.65 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.14 (d,J=8.4 Hz, 1H), 4.52 (m, 1H), 4.12 (s, 3H), 3.14-3.04 (m, 2H), 2.86-2.76(m, 2H), 2.34 (s, 6H), 1.80-1.62 (m, 2H), 1.60-1.42 (m, 5H), 0.93 (d,J=6.3 Hz, 3H), 0.90 (d, J=6.3 Hz, 3H).

EXAMPLE 53(6)

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(3-amino-2,2-dimethylpropyl)carbamoyl]benzoicacid dimethanesulfonate

TLC:Rf 0.34 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ10.62 (s, 1H), 9.19 (s, 2H), 9.00 (t, J=6.3 Hz, 1H), 8.81 (s, 2H), 8.48(d, J=1.5 Hz, 1H), 8.08 (dd, J=7.2, 1.5 Hz, 1H), 7.91 (d, J=9.0 Hz, 2H),7.84-7.72 (m, 3H), 7.79 (d, J=9.0 Hz, 2H), 7.64 (d., J=8.4 Hz, 1H), 7.35(d, J=7.2 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 4.12 (s, 3H), 3.26 (d, J=6.3Hz, 2H), 2.70-2.62 (m, 2H), 2.32 (s, 6H), 1.00 (s, 6H).

EXAMPLE 53(7)

2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(3-amino-1(S)-t-butylpropyl)carbamoyl]benzoicacid dimethanesulfonate

TLC:Rf 0.60 (Ethyl acetate:Acetic acid:Water=3:3:1); NMR (d₆-DMSO): δ12.8-12.3 (brd, 1H), 10.58 (s, 1H), 9.20 (s, 2H), 8.90 (s, 2H), 8.39 (d,J=1.8 Hz, 1H), 8.27 (d, J=9.9 Hz, 1H), 8.02 (dd, J=8.1, 1.8 Hz, 1H),7.88 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.77 (s, 2H), 7.62 (d,J=8.4 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 4.56 (dd,J=12.9, 6.0 Hz, 2H), 3.94 (t, J=10.2 Hz, 1H), 2.78 (m, 2H), 2.32 (s,6H), 1.90 (m, 1H), 1.76 (m, 1H), 1.41 (t, J=6.0 Hz, 3H), 0.95 (s, 9H).

EXAMPLE 53(8)

2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(4-amino-1(S)-t-butylbutyl)carbamoyl]benzoicacid dimethanesulfonate

TLC:Rf 0.60 (Ethyl acetate:Acetic acid:Water=3:3:1); NMR (300 MHz,d₆-DMSO): δ 12.8-12.3 (brd, 1H), 10.58 (s, 1H), 9.20 (s, 2H), 8.88 (s,2H), 8.41 (d, J=1.8 Hz, 1H), 8.16 (d, J=9.6 Hz, 1H), 8.04 (dd, J=7.8,1.8 Hz, 1H), 7.88 (d, J=9.0 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.68 (brd,2H), 7.61 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.10 (d, J=7.8 Hz,1H), 4.56 (m, 2H), 3.83 (m, 1H), 2.80-2.70 (m, 2H), 2.31 (s, 6H),1.68-1.40 (m, 4H), 1.41 (t, J=6.9 Hz, 3H), 0.93 (s, 9H).

EXAMPLE 54

N-hydroxy-2′-(4-amidinophenylcarbamoyl)-4-[(1(R)2,2-trimethylpropyl)carbamoyl]-2-biphenylcarboxamide methanesulfonate

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Example 21→Example 22,using a salt-free compound of a compound prepared in Example 41(12).

TLC:Rf 0.36 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 11.52(br, 1H), 11.22 (s, 1H), 9.15 (s, 2H), 8.91 (s, 2H), 8.11 (d, J=9.6 Hz,1H), 8.02 (d, J=1.5 Hz, 1H), 7.89 (dd, J=7.8, 1.5 Hz, 1H), 7.73-7.68 (m,3H), 7.60-7.54 (m, 4H), 7.22 (d, J=7.8 Hz, 1H), 7.12 (m, 1H), 3.96 (m,1H), 2.38 (s, 3H), 1.07 (d, J=6.6 Hz, 3H), 0.89 (s, 9H).

REFERENCE EXAMPLE 28

Benzyl2′-(4-nitrilebenzyloxy)-4′-methyl-4-[(1(S)-t-butyldimetylsilyloxymethyl-2,2-dimethylpropyl)carboxamide]-2-biphenylcarboxylate

To a solution of a compound (1.10 g) prepared by the same procedure as aseries of reaction of Reference Example 4 using2-(4-formylbenzyloxy)-4-methylphenylboric acid and benzyl2-trifluoromethylsulfonyloxy-5-((1(S)-t-butyidimethylsilyloxymethyl-2,2-dimethylpropyl)carbamoyl)benzoate,in pyridine (20 ml), hydroxylamine hydrochloride (220 mg) and anhydrousacetic acid (0.75 ml) was added. The mixture was stirred for 1.5 hour at90° C. The reaction mixture was diluted with ethyl acetate. The solutionwas washed two times with a saturated aqueous solution of sodiumchloride. The organic layer was dried over anhydrous sodium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=3:1) to give the title compound (1.05g) having the following physical data.

TLC:Rf 0.69 (Hexane:Ethyl acetate=3:1); NMR (200 MHz, CDCl₃): δ 8.31 (d,J=1.8 Hz, 1H), 7.98 (dd, J=8.0, 1.8 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H),7.42 (d, J=8.0 Hz, 1H), 7.3-7.2 (m, 3H), 7.20 (d, J=8.4 Hz, 2H), 7.16(d, J=8.0 Hz, 1H), 7.1-7.0 (m, 2H), 6.90 (br.d, J=8.0 Hz, 1H), 6.7-6.5(m, 1H), 6.60 (br.s, 1H), 5.06 (s, 2H), 4.83 (s, 2H), 4.04 (m, 1H), 3.83(dd, J=10.6, 3.4 Hz, 1H), 3.76 (dd, J=10.6, 4.0 Hz, 1H), 2.37 (s, 3H),1.04 (s, 9H), 0.88 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H).

EXAMPLE 55(1)-55(3)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 20→Example 37→Example 45→Example 38using a compound prepared in Reference Example 28, or were obtained bythe same procedure as a series of reaction of Reference Example4→Reference Example 28→Reference Example 20→Example 37→Example 38 usinga corresponding compounds.

EXAMPLE 55(1)

2′-(4-amidinobenzyloxy)-4-(2-methylpropylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.29 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ12.70 (1H, br.s), 9.24 (2H, br.s), 8.81 (2H, br.s), 8.66 (1H, br.t,J=6.0 Hz), 8.29 (1H, br.s), 8.03 (1H, br.d, J=7.0 Hz), 7.72 (2H, d,J=8.1 Hz), 7.47 (2H, d, J=8.1 Hz), 7.40 (1H, d, J=7.8 Hz), 7.32 (1H,br.t, J=7.8 Hz), 7.21 (1H, br.d, J=7.8 Hz), 7.1-7.0 (2H, m), 5.15 (2H,s), 3.10 (2H, t, J=6.0 Hz), 2.30 (3H, s), 1.85 (1H, like septet, J=6.0Hz), 0.89 (6H, d, J=6.0 Hz).

EXAMPLE 55(2)

2′-(4-amidinobenzyloxy)-4-(1(S)-hydroxymethyl-2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylicacid methanesulfonate

TLC:Rf 0.29 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ9.27 (s, 2H), 8.99 (s, 2H), 8.29 (d, J=1.5 Hz, 1H), 8.09 (d, J=9.3 Hz,1H), 8.05 (dd, J=1.5, 8.1 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.48 (d,J=8.0 Hz, 2H), 7.39 (d, J=8.1 Hz, 1H), 7.32 (dt, J=1.5, 7.5 Hz, 1H),7.20 (dd, J=1.5, 7.5 Hz, 1H), 7.1-7.0 (m, 2H), 5.16 (s, 2H), 4.1-3.6 (m,2H), 3.92 (dt, J=3.3, 9.3 Hz, 1H), 3.67 (dd, J=3.3, 11.4 Hz, 1H), 3.49(dd, J=9.3, 11.4 Hz, 1H), 2.34 (s, 3H), 0.92 (s, 9H).

EXAMPLE 55(3)

2′-(4-amidinobenzyloxy)-4′-methyl-4-(1(S)-hydroxymethyl-2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylic acid methanesulfonate

TLC:Rf 0.70 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ9.27 (s, 2H), 8.96 (s, 2H), 8.27 (d, J=1.8 Hz, 1H), 8.07 (d, J=9.3 Hz,1H), 8.03 (dd, J=8.1, 1.8 Hz, 11H), 7.73 (d, J=8.4 Hz, 2H), 7.48 (d,J=8.4 Hz, 2H), 7.36 (d, J=8.1 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.93 (s,1H), 6.86 (d, J=7.5 Hz, 1H), 5.14 (s, 2H), 3.91 (m, 1H), 4.0-3.6 (br,2H), 3.67 (dd, J=11.4, 3.6 Hz, 1H), 3.48 (dd, J=11.4, 9.0 Hz, 1H), 2.33(s, 3H), 2.33 (s, 3H), 0.91 (s, 9H).

EXAMPLE 56

2′-(4-amidinophenylaminomethyl)-4-(1(S)-hydroxymnethyl-2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylic acid methanesulfonate

The title compound having the following physical data was obtained bythe same procedure as a series of reaction of Reference Example15→Reference Example 16→Example 16→Example 45→Example 2, using benzyl2′-formyl-4-(1(R)-t-butyldimethylsilyloxymethyl-2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylate which was obtained by the sameprocedure as a series of reaction of Reference Example 4 using acorresponding compound.

TLC:Rf 0.54 (Ethyl acetate:Acetic acid:Water=3:1:1); NMR (d₆-DMSO): δ8.74 (2H, br s), 8.36 (1H, d, J=1.4 Hz), 8.31 (2H, br s), 8.12 (1H, d,J=9.2 Hz), 8.07-8.04 (1H, m), 7.52 (2H, d, J=8.8 Hz), 7.44 (1H, d, J=8.0Hz), 7.30-7.26 (4H, m), 7.12-7.06 (1H, m), 6.55 (2H, d, J=8.8 Hz), 4.07(2H, br s), 3.98-3.86 (1H, m), 3.67 (1H, dd, J=4.0,11.2 Hz), 3.55-3.30(2H, m), 2.30 (3H, s), 0.91 (9H, s).

REFERENCE EXAMPLE 29

Benzyl 2-[2-(4-cyanophenylaminomethyl)-3-pyridyl]-5-(2-methylpropylcarbamoyl)benzoate

Benzyl 2-(2-formyl-3-pyridyl)-5-(2-methylpropylcarbamoyl)benzoate (674mg) which was obtained by the same procedure as a series of reaction ofReference Example 4 using a corresponding compound, and 4-cyanoaniline(382 mg) were dissolved into ethanol (3 ml) and acetic acid (3 ml).Sodium cyanoborohydride (153 mg) was slowly added to the mixture at 0°C. The mixture was stirred for 30 minutes, and was made to more pH 8 byadding 1N aqueous solution of sodium hydroxide. A saturated aqueoussolution of sodium bicarbonate was added to the solution. The solutionwas extracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium bicarbonate and a saturated aqueoussolution of sodium chloride, successively, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=2:1→1:1) to give thetitle compound (692 mg) having the following physical data.

TLC:Rf 0.21 (Hexane:Ethyl acetate=1:1); NMR (CDCl₃): δ 8.55 (d, J=1.8Hz, 1H), 8.44 (d, J=1.8 Hz, 1H), 8.05 (dd, J=8.1, 1.8 Hz, 1H), 7.40 (dd,J=7.8, 1.8 Hz, 1H), 7.4-7.3 (m, 3H), 7.3-7.2 (m, 4H), 7.1-7.0 (m, 2H),6.43 (d, J=8.7 Hz, 2H), 6.30 (br.t, J=6.6 Hz, 1H), 5.80 (br.t, J=4.5 Hz,1H), 5.03 (s, 2H), 4.04 (dd, J=15.6, 4.5 Hz, 1H), 3.95 (dd, J=15.6, 3.9Hz, 1H), 3.35 (t, J=6.6 Hz, 2H), 1.95 (like septet, J=6.6 Hz, 1H), 1.02(d, J=6.6 Hz, 3H), 1.02 (d, J=6.6 Hz, 3H).

REFERENCE EXAMPLE 30

Benzyl 2-[2-(4-(im ino-ethoxymethyl)phenylaminomethyl)-3-pyridyl]-5-(2-methyl propylcarbamoyl)benzoate hydrochloride

The compound prepared in Reference Example 29 (681 mg) was dissolvedinto ethanol (7 ml) and methylene chloride (7 ml), and the mixture wasstirred at −20° C. Chloride gas was blown into the mixture slowly for 1hour to be the solution was under 18° C. The solution was sealed up, andallowed to stand for 27 hours at 5° C. The reaction mixture wasconcentrated to give the title compound (643 mg) having the followingphysical data.

TLC:Rf 0.61 (Chloroform:Methanol:Water=9:1:0.1).

EXAMPLE 57

Benzyl 2-[2-(4-amidinophenylaminomethyl)-3-pyridyl]-5-(2-methylpropylcarbamoyl)benzoate

The compound prepared in Reference Example 30 (643 mg) was dissolvedinto ethanol (25 ml), and the solution was stirred at 0° C. An ammoniumgas was blown into the mixture slowly for 15 minutes to be the solutionwas under 20° C. The solution was sealed up, and allowed to stand for 28hours at room temperature. The reaction mixture was concentrated. Theresidue was purified by column chromatography on silica gel(Chloroform:Methanol=10:1→Chloroform:Methanol:Water=10:2:0.1) to givethe title compound (307 mg) having the following physical data.

TLC:Rf 0.68 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ8.77 (t, J=6.0 Hz, 1H), 8.9-8.4 (br, 3H), 8.52 (dd, J=4.8, 1.5 Hz, 1H),8.47 (d, J=1.8 Hz, 1H), 8.13 (dd, J=7.8, 1.8 Hz, 1H), 7.53 (d, J=9.0 Hz,2H), 7.6-7.45 (m, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.35-7.25 (m, 4H),7.2-7.1 (m, 2H), 6.98 (t, J=5.4 Hz, 1H), 6.53 (d, J=9.0 Hz, 2H), 5.07(d, J=14.4 Hz, 1H), 5.04 (d, J=14.4 Hz, 1H), 4.2-4.0 (m, 2H), 3.11 (t,J=6.0 Hz, 2H), 1.87 (like septet, J=6.6 Hz, 1H), 0.90 (d, J=6.6 Hz, 3H),0.90 (d, J=6.6 Hz, 3H).

EXAMPLE 58

2-[2-(4-amidinophenylaminomethyl)-3-pyridyl]-5-(2-methylpropylcarbamoyl)benzoic acid methanesulfonate

The title compound was obtained by the same procedure as a series ofreaction of Example 2, using a compound prepared in Example 57.

TLC:Rf 0.26 (Chloroform:Methanol:Acetic acid=10:2:1); NMR (d₆-DMSO): δ8.81 (br.s, 2H), 8.77 (t, J=6.0 Hz, 1H), 8.64 (dd, J=5.1, 1.2 Hz, 1H),8.51 (d, J=1.8 Hz, 1H), 8.49 (br.s, 2H), 8.13 (dd, J=8.0, 1.8 Hz, 1H),7.87 (br.d, 1H), 7.62 (br.t, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.51 (d, J=8.0Hz, 1H), 6.58 (d, J=9.0 Hz, 2H), 4.32 (d, J=16.5 Hz, 1H), 4.22 (d,J=16.5 Hz, 1H), 4.4-3.5 (br, 2H), 3.12 (t, J=6.6 Hz, 2H), 2.33 (s, 3H),1.87 (like septet, J=6.6 Hz 1H), 0.90 (d, J=6.6 Hz, 3H), 0.90 (d, J=6.6Hz, 3H).

EXAMPLE 59 (1)-59 (2)

The following compounds were obtained by the same procedure as a seriesof reaction of Reference Example 29→Reference Example 30→Example57→Example 58, using a corresponding compound.

EXAMPLE 59(1)

2-[2-(4-amidinophenylaminomethyl)-6-methyl-3-pyridyl]-5-(2-methylpropylcarbamoyl)benzoic acid methanesulfonate

TLC:Rf 0.58 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆DMSO): δ 8.81(brs, 2H), 8.56 (brt, J=6.0 Hz, 1H), 8.54 (brs, 2H), 8.50 (d, J=1.5 Hz,1H), 8.10 (dd, J=8.0, 1.5 Hz, 1H), 7.96 (brd, J=7.5 Hz, 1H), 7.64 (brd,J=7.5 Hz, 1H), 7.54 (d, J=9.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 1H), 6.51 (d,J=9.0 Hz, 2H), 4.34 (brs, 2H), 3.11 (brt, J=6.0 Hz, 2H), 2.72 (s, 3H),2.35 (s, 3H), 1.93-1.79 (m, 1H), 0.89 (d, J=6.6 Hz, 6H).

EXAMPLE 59(2)

2-[4-(4-amidinophenylaminomethyl)-3-pyridyl]-5-(2-methylpropylcarbamoyl) benzoic acidmethanesulfonate

TLC:Rf 0.36 (Chloroform:Methanol:Water=7:3:0.3); NMR (d₆-DMSO): δ 8.88(brs, 2H), 8.83 (brt, J=6.0 Hz, 1H), 8.78 (d, J=5.7 Hz, 1H), 8.71 (s,1H), 8.63 (brs, 2H), 8.59 (d, J=1.8 Hz, 1H), 8.22 (dd, J=8.0, 1.8 Hz,1H), 7.72 (d, J=5.7 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.59 (d, J=9.0 Hz,2H), 6.58 (d, J=9.0 Hz, 2H), 4.32 (brd, J=18 Hz, 1H), 4.14 (brd, J=18Hz, 1H), 3.13 (brt, J=6.0 Hz, 2H), 2.35 (s, 3H), 1.95-1.81 (m, 1H), 0.90(d, J=6.6 Hz, 6H).

FORMULATION EXAMPLE 1

The following components were admixed in conventional method and punchedout to obtain 100 tablets each containing 100 mg of active ingredient.

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5- 10.0 g[(1(S)-hydroxy methyl-2, 2-dimethylpropyl)carbamoyl]benzoic acidmethanesulfonate Carboxymethyl Cellulose calcium (disintegrating agent) 0.2 g Magnesium stearate (lubricating agent)  0.1 g Microcrystallinecellulose  9.7 g

FORMULATION EXAMPLE 2

The following components were admixed in conventional method. Thesolution was sterilized in conventional manner, placed 5 ml portionsinto ampoules and freeze-dried to obtain 100 ampoules each containing 20mg of the active ingredient.

2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl] 2.0 g-5-[(1(S)-hydroxy methyl-2, 2-dimethylpropyl)carbamoyl] benzoic acidmethanesulfonate mannitol 5.0 g distilled water 1000 ml

What is claimed is:
 1. An amidino compound of the formula (I):

wherein R¹ and R² each independently, is 1) hydrogen, 2) hydroxy, 3)C1-4 alkoxycarbonyl, 4) C2-4 alkenyloxycarbonyl, 5) C1-4alkoxycarbonyloxy or 6) —COO—(C1-4 alkyl)-phenyl,  with the proviso thatwhen R¹ is group excepting hydrogen, R² is hydrogen, or when R² is groupexcepting hydrogen, R¹ is hydrogen R³ is 1) hydrogen, 2) C1-4 alkyl, 3)hydroxy, 4) —O—(C1-4 alkyl)-phenyl, or 5) halogen atom, E¹ ring is 1)5-7 membered unsaturated carbocyclic ring or 2) 5-7 membered unsaturatedheterocyclic ring E² ring is 1) 5-7 membered unsaturated carbocyclicring or 2) 5-7 membered unsaturated heterocyclic ring; E³ ring is 1)absent, 2) 5-7 membered unsaturated or saturated carbocyclic ring or 3)5-7 membered unsaturated or saturated heterocyclic ring; E⁴ ring is 1)5-6 membered unsaturated carbocyclic ring or 2) 5-6 membered unsaturatedheterocyclic ring; R4 and R5 each independently, is 1) —COOR⁸, in whichR⁸ is hydrogen, C1-8 alkyl, —(C1-4 alkyl)-phenyl or —(C1-4alkyl)—O—(C1-4 alkyl); 2) —(C1-4 alkyl)—COOR⁹, in which R⁹ is hydrogen,C1-8 alkyl—(C1-4 alkyl)-phenyl or —(C1-4 alkyl)—O—(C1-4 alkyl); 3)—(C2-4 alkenyl)—COOR¹⁰, in which R¹⁰ is hydrogen, C1-8 alkyl—(C1-4alkyl)-phenyl or —(C1-4 alkyl)—O—(C1-4 alkyl); 4) —O—(C1-4alkyl)—COOR¹¹, in which R¹¹ is hydrogen, C1-8 alkyl—(C1-4 alkyl)-phenylor —(C1-4 alkyl)—O—(C1-4 alkyl); 5) —CONR¹²R ¹³, in which R¹² ishydrogen, C1-4 alkyl, R¹³ is hydroxy, —O—(C1-4 alkyl)-phenyl or cyano;6) —P(O)(OR¹⁴)₂, in which R¹⁴ is hydrogen, C1-4 alkyl or —(C1-4alkyl)-phenyl; or 7) tetrazol -5-yl which is optionally substituted byC1-8 alkyl; p and q each independently, is 0 or 1-2, with the provisothat p+q is 1 or 2; R⁶ and R⁷ each independently, is 1) hydrogen, 2)C1-8 alkyl, 3) nitro, 4) cyano, 5) halogen atom, 6) —(C1-4alkyl)—O—(C1-4 alkyl)-phenyl, 7) —NR¹⁵R¹⁶, in which R¹⁵ and R¹⁶ eachindependently, is hydrogen or C1-8 alkyl; 8) —OR¹⁷, in which R¹⁷ ishydrogen, C1-8 alkyl, CF₃, C2-5 acyl, —(C1-4 alkyl)-phenyl, —(C1-4alkyl)—OH, —(C1-4 alkyl)—O—(C1-4 alkyl), or —(C1-4 alkyl)—O—(C1-4alkyl)—O—(C1-4 alkyl); 9) —(C1-4 alkyl)—OR¹⁷, in which R¹⁷ is ashereinbefore defined; 10) —J¹-J², in which J¹ is (1) —CONR¹⁸—, in whichR¹⁸ is hydrogen or C1-4 alkyl; (2) —NR¹⁹CO—, in which R¹⁹ is hydrogen orC1-4 alkyl; (3) —SO₂NR²⁰—, in which R²⁰ is hydrogen or C1-4 alkyl; (4)—NR²¹SO₂—, in which R²¹ is hydrogen or C1-4 alkyl; (5) —(C1-4alkyl)—NR²²—, in which R²² is hydrogen or C1-4 alkyl; (6) —CO—, (7)—(C1-4 alkyl)—NR²³CO—, in which R²³ is hydrogen or C1-4 alkyl; J² is (1)C1-15 alkyl optionally substituted by 1-3 of following groups (i)-(x):(i) C3-7 cycloalkyl optionally substituted by —(C1-4 alkyl)—OR²⁴; (ii)phenyl, (iii) 5-7 membered saturated heterocyclic ring optionallysubstituted by carboxyl or C1-4 alkoxycarbonyl; (iv) OR²⁴, in which R²⁴is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl)-phenyl, C2-5 acyl, or —(C1-4alkyl)-phenyl; (v) NR²⁵R²⁶, in which R²⁵ is hydrogen or C1-4 alkyl, R²⁶is hydrogen, C1-4 alkyl, —COO(C1-4 alkyl)-phenyl, imino(C1-4 alkyl) orC1-4 alkoxycarbonyl; (vi) —S(O)_(r)—(C1-4 alkyl), in which r is 0-2;(vii) —COOR²⁷, in which R²⁷ is hydrogen, C1-4 alkyl or —(C1-4alkyl)-phenyl; (viii) —CONR²⁸R²⁹, in which R²⁸ and R²⁹ eachindependently, is  (i) hydrogen, (ii) C1-4 alkyl, (iii) hydroxy, or (iv)C1-4 alkyl substituted by one of hydroxy, phenyl or NR²⁵R²⁶, or R²⁸ andR²⁹ taken together with the nitrogen atom to which they are attachedform 5-6 membered saturated heterocyclic ring containing nitrogen atom(ix) halogen atom, (x) trihalomethyl; (2) C2-8 alkenyl, (3) C5-7cycloalkyl optionally substituted by 1-3 of C1-4 alkyl, —COOR²⁷, inwhich R²⁷ is as hereinbefore defined; —(C1-4 alkyl)—OR²⁴, in which R²⁴is as hereinbefore defined; (4) —NR²⁵R²⁶, in which R²⁵ and R²⁶ is ashereinbefore defined; (5) 5-6 membered saturated heterocyclic ringoptionally substituted by 1-3 of C1-4 alkyl, oxo, imino(C1-4 alkyl); orR¹⁸ and J² taken together with the nitrogen atom to which they areattached form saturated heterocyclic ring optionally substituted by 1-3of C1-8 alkyl, C2-8 alkenyl or —COOR²⁷, in which R²⁷ is as hereinbeforedefined; m is 1-3; n is 1-3; two R⁶ taken together with the neighboringtwo carbon of E⁴ ring to which they are attached form 5-6 memberedunsaturated carbocyclic ring or 5-6 membered saturated heterocyclicring, that rings may be substituted by 1-3 of R⁴ or R⁶; A is 1)ethylene, 2) vinylene, 3) ethynylene, 4) —O—CH₂—, 5) —CH₂—O—, 6)—NR³⁰CO—, in which R³⁰ is hydrogen or C1-4 alkyl 7) —NR³¹CHR³²—, inwhich R³¹ is hydrogen or C1-4 alkyl, R³² is hydrogen, cyano, COOR³⁶, inwhich R³⁶ is hydrogen or C1-4 alkyl; or CONR³⁷R³⁸, in which R³⁷ and R³⁸each independently, is hydrogen or C1-4 alkyl; 8) —CH₂—NR³³—, in whichR³³ is hydrogen or C1-4 alkyl; 9) —S—CH₂—, 10) —CH₂—S—, 11) —SO₂NR³⁴—,in which R³⁴ is hydrogen or C1-4 alkyl; 12) —NR³⁵SO₂—, in which R³⁵ ishydrogen or C1-4 alkyl; non-toxic salts thereof, or hydrates thereof. 2.A compound according to claim 1, wherein in E³ ring is absent in theformula:


3. A compound according to claim 1, wherein E³ ring is 5-7 memberedunsaturated or saturated carbocyclic ring or 5-7 membered unsaturated orsaturated heterocyclic ring in the formula:


4. A compound according claim 1, wherein A is —CH₂—O—, —NR³⁰CO— or—NR³¹CHR³²—.
 5. An amidino compound according to claim 1 of the formula(I-1):

wherein R¹ and R² each independently, is 1) hydrogen, 2) hydroxy, 3)C1-4 alkoxycarbonyl, 4) C2-4 alkenyloxycarbonyl, 5) C1-4alkoxycarbonyloxy or 6) —COO—(C1-4 alkyl)-phenyl,  with the proviso thatwhen R¹ is group excepting hydrogen, R² is hydrogen, or when R² is groupexcepting hydrogen, R¹ is hydrogen; R³ is 1) hydrogen, 2) C1-4 alkyl, 3)hydroxy, 4) —O—(C1-4 alkyl)-phenyl, or 5) halogen atom; E¹ ring is 1)5-7 membered unsaturated carbocyclic ring or 2) 5-7 membered unsaturatedheterocyclic ring; E² ring is 1) 5-7 membered unsaturated carbocyclicring or 2) 5-7 membered unsaturated heterocyclic ring; E⁴ ring is 1) 5-6membered unsaturated carbocyclic ring or 2) 5-6 membered unsaturatedheterocyclic ring; R⁴ and R⁵ each independently, is 1) —COOR⁸, in whichR⁸ is hydrogen, C1-8 alkyl, —(C1-4 alkyl)-phenyl or —(C1-4alkyl)—O—(C1-4 alkyl); 2) —(C1-4 alkyl)—COOR⁹, in which R⁹ is hydrogen,C1-8 alkyl, —(C1-4 alkyl)-phenyl or —(C1-4 alkyl)—O—(C1-4 alkyl); 3)—(C2-4 alkenyl)—COOR¹⁰, in which R¹⁰ is hydrogen, —C1-8 alkyl, (C1-4alkyl)-phenyl or —(C1-4 alkyl)—O—(C1-4 alkyl); 4) —O—(C1-4alkyl)—COOR¹¹, in which R¹¹ is hydrogen, C1-8 alkyl, —(C1-4alkyl)-phenyl or —(C1-4 alkyl)—O—(C1-4 alkyl); 5) —CONR¹²R¹³, in whichR¹² is hydrogen, C1-4 alkyl, R¹³ is hydroxy, —O—(C1-4 alkyl)-phenyl orcyano; 6) —P(O)(OR¹⁴)₂, in which R¹⁴ is hydrogen, C1-4 alkyl or —(C1-4alkyl)-phenyl; or 7) tetrazol -5-yl which is optionally substituted byC1-8 alkyl; pp and qq each independently, is 0 or 1, with the provisothat pp+qq is 0 or 1; R⁶ and R⁷ each independently, is 1) hydrogen, 2)C1-8 alkyl, 3) nitro, 4) cyano, 5) halogen atom, 6) —(C1-4alkyl)—O—(C1-4 alkyl)-phenyl, 7) —NR¹⁵R¹⁶, in which R¹⁵ and R¹⁶ eachindependently, is hydrogen or C1-8alkyl; 8) —OR¹⁷, in which R¹⁷ ishydrogen, C1-8 alkyl, CF₃, C2-5 acyl, —(C1-4 alkyl)-phenyl, —(C1-4alkyl)—OH, —(C1-4 alkyl)—O—(C1-4 alkyl), or —(C1-4 alkyl)—O—(C1-4alkyl)—O—(C1-4 alkyl); 9) —(C1-4 alkyl)—OR¹⁷, in which R¹⁷ is ashereinbefore defined; 10) —J¹-J², in which J¹ is (1) —CONR¹⁸—, in whichR¹⁸ is hydrogen or C1-4 alkyl; (2) —NR¹⁹CO—, in which R¹⁹ is hydrogen orC1-4 alkyl; (3) —SO₂NR²⁰—, in which R²⁰ is hydrogen or C1-4 alkyl; (4)—NR²¹SO₂—, in which R²¹ is hydrogen or C1-4 alkyl; (5) —(C1-4alkyl)—NR²²—, in which R²² is hydrogen or C1-4 alkyl; (6) —CO—, (7)—(C1-4 alkyl)—NR²³CO—, in which R²³ is hydrogen or C1-4 alkyl; J²is (1)C1-15 alkyl optionally substituted by 1-3 of following groups (i)-(x):(i) C3-7 cycloalkyl optionally substituted by —(C1-4 alkyl)—OR²⁴; (ii)phenyl, (iii) 5-7 saturated heterocyclic ring optionally substituted bycarboxyl or C1-4 alkoxycarbonyl; (iv) OR²⁴, in which R²⁴ is hydrogen,C1-4 alkyl, —COO—(C1-4 alkyl)-phenyl, C2-5 acyl, or —(C1-4alkyl)-phenyl; (v) NR²⁵R²⁶, in which R²⁵ is hydrogen or C1-4 alkyl, R²⁶is hydrogen, C1-4 alkyl, —COO(C1-4 alkyl)-phenyl, imino(C1-4 alkyl) orC1-4 alkoxycarbonyl (vi) —S(O)_(r)—(C1-4 alkyl), in which r is 0-2;(vii) —COOR²⁷, in which R²⁷ is hydrogen, C1-4 alkyl or —(C1-4alkyl)-phenyl; (viii) —CONR²⁸R²⁹, in which R²⁹ and R²⁹ eachindependently, is  (i) hydrogen, (ii) C1-4 alkyl, (iii) hydroxy, or (iv)C1-4 alkyl substituted by one of hydroxy, phenyl or NR²⁵R²⁶, or R²⁸ andR²⁹ taken together with the nitrogen atom to which they are attachedform 5-6 membered saturated heterocyclic ring containing nitrogen atom;(ix) halogen atom, (x) trihalomethyl; (2) C2-8 alkenyl, (3) C5-7cycloalkyl optionally substituted by 1-3 of C1-4 alkyl, —COOR²⁷, inwhich R²⁷ is as hereinbefore defined; —(C1-4 alkyl)—OR²⁴, in which R²⁴is as hereinbefore defined; (4) —NR²⁵R²⁶, in which R₂₅ and R²⁶ is ashereinbefore defined; (5) 5-6 membered saturated heterocyclic ringoptionally substituted by 1-3 of C1-4 alkyl, oxo, imino(C1-4 alkyl); orR¹⁸ and J² taken together with the nitrogen atom to which they areattached form saturated heterocyclic ring optionally substituted by 1-3of C1-8 alkyl, C2-8 alkenyl or —COOR²⁷, in which R²⁷ is as hereinbeforedefined; m is 1-3; n is 1-3; two R⁶ taken together with the neighboringtwo carbon of E⁴ ring to which they are attached form 5-6 memberedunsaturated carbocyclic ring or 5-6 membered saturated heterocyclicring, that rings may be substituted by 1-3 of R⁴ or R⁶; A^(a) is 1)—CH₂—O—, 6) —NR³⁰CO—, 7) —NR³¹CHR³²; with the proviso that A^(a) and E⁴ring attach to E² ring at ortho position, E² ring and essential one R⁴attach to E⁴ ring at ortho position; non-toxic salts thereof, orhydrates thereof.
 6. A compound according to claim 1, wherein at leastone of R⁶ is —J¹-J².
 7. A compound according to claim 1, which isselected from (1)2′-(4-amidinophenylcarbamoyl)-4-((2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (2)2′-(4-amidinophenylcarbamoyl)-4-dimethylcarbamoyl-2-biphenylcarboxylicacid, (3)2′-(4-amidinophenylcarbamoyl)-4-methylcarbamoyl-2-biphenylcarboxylicacid, (4)2′-(4-amidinophenylcarbamoyl)-4-((carboxymethyl)carbamoyl)-2-biphenylcarboxylicacid, (5)2′-(4-amidinophenylcarbamoyl)-4-((1-carboxy-2-phenylethyl)carbamoyl)-2-biphenylcarboxylicacid, (6)2′-(4-amidinophenylcarbamoyl)-4-benzylcarbamoyl-2-biphenylcarboxylicacid, (7)2′-(4-amidinophenylcarbamoyl)-4-phenylethylcarbamoyl-2-biphenylcarboxylicacid, (8)2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (9)2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (10)2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (11)2′-(4-amidinophenylcarbamoyl)-4-isopropylcarbamoyl-2-biphenylcarboxylicacid, (12)2′-(4-amidinophenylcarbamoyl)-4-((3-methylbutyi)carbamoyl)-2-biphenylcarboxylicacid, (13)2′-(4-amidinophenylcarbamoyl)-4-ethylcarbamoyl-2-biphenylcarboxylicacid, (14) 2′-(4-amidinophenylcarbamoyl)-4-butylcarbamoyl-2-biphenylcarboxylic acid, (15)2′-(4-amidinophenylcarbamoyl)-4′-methyl-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (16)2′-(4-amidinophenylcarbamoyl)-4-((cyclohexylmethyl)carbamoyl)-2-biphenylcarboxylicacid, (17)2′-(4-amidinophenylcarbamoyl)-4-((5-(t-butoxycarbonylamino)pentyi)carbamoyl)-2-biphenylcarboxylicacid, (18)2′-(4-amidinophenylcarbamoyl)-4-((1-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (19)2′-(4-amidinophenylcarbamoyl)-4-((tetrahydropyran-4-ylmethyl)carbamoyl)-2-biphenylcarboxylicacid, (20)2′-(4-amidinophenylcarbamoyl)-4-((2-hydroxypropyl)carbamoyl)-2-biphenylcarboxylicacid, (21)2′-(4-amidino-2-hydroxyphenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (22)2′-(4-amidinophenylcarbamoyl)-4-(N-methyl-N-(2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (23)2′-(4-amidinophenylcarbamoyl)-4-((2-methyl-1-(methylaminomethyl)propyl)carbamoyl)-2-biphenylcarboxylic acid, (24)2′-(4-amidinophenylcarbamoyl)-4-((2-hydroxy-2-methylpropyl)carbamoyl)-2-biphenylcarboxylic acid, (25) 2′-(4-amidino-2-mrethyiphenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (26)2′-(4-amidinophenylcarbamoyl)-4-((cyclopropylmethyl)carbamcyl)-2-biphenylcarboxylicacid, (27)2′-(4-amidinophenylcarbamoyl)-4-((1-methylcarbamoyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (28)2′-(4-amidinophenylcarbamoyl)-4-((cyclopentylmethyl)carbamoyl)-2-biphenylcarboxylicacid, (29)2′-(4-amidinophenylcarbamoyl)-4-((cyclobutylmethyl)carbamoyl)-2-biphenylcarboxylicacid, (30)2′-(4-amidinophenylcarbamoyl)-4-((1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (31)2′-(4-amidinophenylcarbamoyl)-4-((2-methoxycarbonylethyl)carbamoyl)-2-biphenylcarboxylicacid, (32)2′-(4-amidinophenylcarbamoyl)-4-((3-ethoxycarbonylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (33)2′-(4-amidinophenylcarbamoyl)-4-((1-t-butoxycarbonylpiperidin-4-ylmethyl)carbamoyl)-2-biphenylcarboxylicacid, (34)2′-(4-amidinophenylcarbamoyl)-4-((2-methyithioethyl)carbamoyl)-2-biphenylcarboxylicacid, (35)2′-(4-amidinophenylcarbamoyl)-4-((2-methylsulfinylethyl)carbamoyl)-2-biphenylcarboxylicacid, (36)2′-(4-amidinophenylcarbamoyl)-4-((1-dimethylaminomethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (37)2′-(4-amidinophenylcarbamoyl)-4-((1-(pyrrolidin-1-ylmethyl)-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (38)2′-(4-amidinophenylcarbamoyl)-4-((1-hydroxymethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (39)2′-(4-amidinophenylaminomethyl)-4-((2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (40)2′-(4-amidinophenylaminomethyl)-4′-methoxy-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (41)2′-(4-amidinophenylaminomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (42)2′-(4-amidinophenylaminomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (43)2′-(4-(N²-hydroxyamidino)phenylaminomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (44)2′-(4-(N²-hydroxyamidino)phenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (45)2-(4-(4-amidinophenylcarbamoyl)pyridin-3-yl)-5-((2-methylpropyl)carbamoyl)benzoicacid, (46)2′-(4-amidinophenylcarbamoyl)-4-propylcarbamoyl-2-biphenylcarboxylicacid, (47)2′-(4-amidinophenylcarbamoyl)-4-((3-hydroxy-2,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (48)2′-(4-amidinophenylcarbamoyl)-4-((1,2,2-trimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (49)2′-(4-amidinophenylcarbamoyl)-4-pentylcarbamoyl-2-biphenylcarboxylicacid, (50)2′-(4-amidinophenylcarbamoyl)-4-hexylcarbamoyl-2-biphenylcarboxylicacid, (51)2′-(4-amidinophenylcarbamoyl)-4-((1,2-dimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (52)2′-(4-amidinophenylcarbamoyl)-4-(((1S)-1-hydroxymethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (53)2′-(4-amidinophenylcarbamoyl)-4-((3,3-dimethylbutyl)carbamoyl)-2-biphenylcarboxylicacid, (54)2′-(4-amidinophenylcarbamoyl)-4-(((1R)-1-hydroxymethyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (55)2′-(4-amidinophenylcarbamoyl)-4-(((1S)-1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (56)2′-(4-amidinophenylcarbamoyl)-4-(((1R)-1-methoxycarbonyl-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (57)2-(3-(4-amidinophenylcarbamoyl)pyridin-4-yl)-5-((2-methylpropyl)carbamoyl)benzoicacid, (58)2′-(6-amidinopyridin-3-yl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (59)2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((1,2,2-trimethyipropyl)carbamoyl)-2-biphenylcarboxylicacid, (60)2′-(4-amidinophenylcarbamoyl)-4-(((1S)-1-hydroxymethyl-2,2-dimethylpropyi)carbamoyl)-biphenylcarboxylicacid, (61)2′-(6-amidinopyridin-3-ylcarbamoyl)-2-((1,2,2-trimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (62)2′-(4-amidinophenylcarbamoyl)-4-((1-carboxy-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (63)2′-(4-amidinophenylcarbamoyl)-4-((2-carboxyethyl)carbamoyl)-2-biphenylcarboxylicacid, (64)2′-(4-amidinophenylcarbamoyl)-4-((3-carboxypropyl)carbamoyl)-2-biphenylcarboxylicacid, (65)2′-(4-amidinophenylcarbamoyl)-4-((5-aminopentyl)carbamoyl)-2-biphenylcarboxylicacid, (66)2′-(4-aridinophenylcarbamoyl)-4-((piperidin-4-ylmethyl)carbamoyl)-2-biphenylcarboxylicacid, (67)2′-(6-amidinopyridin-3-ylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (68)2′-(6-amidinopyridin-3-ylcarbamoyl)-4′-methoxy-4-((1,2,2-trimethylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (69)N-hydroxy-2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxamide,(70)N-hydroxy-2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxamide,(71)2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1,2,2-trimethylpropyl)carbamoyl]benzoicacid, (72)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(2-methylpropyl)carbamoyl]benzoicacid, (73)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1,2,2-trimethylpropyl)carbamoyl]benzoicacid, (74)2′-(4-amidinophenylcarbamoyl)-4-(1,1-dimethylpropylcarbamoyl)-2-biphenylcarboxylicacid, (75)2′-(4-amidinophenylcarbamoyl)-4-[(1(S)-t-butyl-2-methoxycarbonylethyl)carbamoyl]-2-biphenylcarboxylicacid, (76)2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethylcyclohexylcarbamoyl)-2-biphenylcarboxylicacid, (77)2′-(4-amidinophenylcarbamoyl)-4-(1-isopropyl-2-methylpropylcarbamoyl)-2-biphenylcarboxylicacid, (78)2′-(4-amidinophenylcarbamoyl)-4-[(4,4-dimethyloxolan-3(S)-yl)carbamoyl]-2-biphenylcarboxylicacid, (79)2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(2-methylpropyl)carbamoyl]benzoicacid, (80)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(3-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (81)2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1,2,2-trimethylpropyl)carbamoyl]benzoicacid, (82) 2′-(4-amidinophenylcarbamoyl)-4-[(1(R),2,2-trimethylpropyi)carbamoyl]-2-biphenylcarboxylic acid, (83)2′-(4-amidinophenylcarbamoyl)-4-[(1(S),2,2-trimethylpropyl)carbamoyl]-2-biphenylcarboxylic acid, (84)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(2,2-dimethylpropyl)carbamoyl]benzoicacid, (85)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-methylpropyl)carbamoyl]benzoicacid, (86)2′-(4-amidinophenylcarbamoyl)-4-(1-methoxycarbonylcyclopentylcarbamoyl)-2-biphenylcarboxylicacid, (87)2˜14-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-hydroxymethyl-2-methylpropyl)carbamoyl]benzoicacid, (88)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1(S)-hydroxymethyl-2-methylpropyl)carbamoyl]benzoicacid, (89)2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-hydroxymethyl-2-methylpropyl)carbamoyl]benzoicacid, (90)2′-(4-amidinophenylcarbamoyl)-4-[(2-methoxycarbonyl-2,2-dimethylethyl)carbamoyl]-2-biphenylcarboxylicacid, (91)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1(S)-methoxycarbonyl-2-methylpropyl)carbamoyl]benzoicacid, (92)2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-methoxycarbonyl-2-methylpropyl)carbam oyl]benzoic acid, (93)2′-(4-amidino-3-hydroxyphenylcarbamoyl)-4-(2-methylpropylcarbamoyl)-2-biphenylcarboxylicacid, (94)2′-(4-amidino-3-hydroxyphenylcarbamoyl)-4-(1,2,2-trimethylpropylcarbamoyl)-2-biphenylcarboxylicacid, (95)2′-(4-amidinophenylcarbamoyl)-4-(1,3-dimethylbutylcarbamoyl)-2-biphenylcarboxylicacid, (96)2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethyl-1(R)-cyclopentylcarbamoyl)-2-biphenylcarboxylicacid, (97)2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-carboxy-2-methylpropyl)carbamoyl]benzoicacid, (98)2-[3-(4-amidinophenylcarbamoyl)-2-furyl]-5-(2-methylpropylcarbamoyl)benzoicacid, (99)2-[2-(4-amidinophenylcarbamoyl)-3-thienyl]-5-(2-methylpropylcarbamoyl)benzoicacid, (100)2′-(4-amidinophenylcarbamoyl)-4-[(1-methoxycarbonyl-1-methylethyl)carbamoyl]-2-biphenylcarboxylicacid, (101)2′-(4-amidinophenylcarbamoyl)-4-(1(S)-carboxy-3-methylbutylcarbamoyl)-2-biphenylcarboxylicacid, (102)2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoicacid, (103)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoicacid, (104)2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethyl-1(S)-cyclopentylcarbamoyl)-2-biphenylcarboxylicacid, (105)2-[3-(4-amidinophenylcarbamoyl)-2-thienyl]-5-(2,2-dimethylpropylcarbamoyl)benzoicacid, (106)2-[2-(4-amidinophenylcarbamoyl)-3-thienyl]-5-(2,2-dimethylpropylcarbamoyl)benzoicacid, (107)2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoicacid, (108)2-[2-(4-amidinophenylcarbamoyl)-5-methyl-3-thienyl]-5-(2,2-dimethylpropylcarbamoyl)benzoicacid, (109)2′-(4-amidinophenylcarbamoyl)-4′-amino-4-(2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylicacid, (110)2-[2-(4-amidinophenylcarbamoyl)-5-methyl-3-furyl]-5-(2,2-dimethylpropylcarbamoyl)benzoicacid, (111)2-[4-(4-amidinophenylcarbamoyl)-2-methyl-pyrimidin-5-yl]-5-(2,2-dimethylpropylcarbamoyl)benzoicacid, (112)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(1(S)-morpholinocarbonyl-3-methylbutylcarbamoyl)benzoicacid, (113)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(1(S)-methoxymethyl-2,2-dimethylpropylcarbamoyl)benzoicacid, (114)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(1(S)-methoxymethyl-2,2-dimethylpropylcarbamoyl)benzoicacid, (115)2-[2-(4-amidino-3-fluorophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoicacid, (116)2′-(4-amidinophenylcarbamoyl)-5′-amino-4-(2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylicacid, (117)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(1,1,3,3-tetramethylbutylcarbamoyl)benzoicacid, (118)2-[2-(4-amidinophenylcarbamoyl)-5-methyl-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoicacid, (119)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[5-(1-methylethyl)-2,2-dimethyidioxan-5-yl]carbamoyl]benzoicacid, (120)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[1(S)-(4-ethoxycarbonyloxazol-2-yl)-3-methylbutyl)carbamoyl]benzoicacid, (121)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-N-hydroxycarbamoyl)-3-methylbutylcarbamoyl]benzoicacid, (122)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)-4-methylbenzoicacid, (123)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(1(S)-hydroxymethyl-3-methylbutytcarbamoyl)-4-methylbenzoicacid, (124)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(4,4-dimethyioxolan-3(S)-yl)carbamoyl]-4-methylbenzoicacid, (125)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(1(R),2,2-trimethylpropylcarbamoyl)benzoic acid, (126)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl[3-5-[(1(R)-2,2-dimethylcyclopentyl)carbamoyl]benzoicacid, (127)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-methylaminomethyl-3-methylbutyl)carbamoyl]benzoicacid, (128)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl)-5-[(4,4-dimethyl-2-oxooxolan-3(S)-yl)carbamoyl]benzoicacid, (129)2-[2-(4-amidinophenylcarbamoyl)-3-thienyl]-5-[(1(S)-acetyloxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (130)2-[2-(4-amidinophenylcarbamoyl-6-methoxy-3-pyridyl]-5-[[4-carboxy-4-(2-methyl-2-propenyl)piperidinyl]carbonyl]benzoicacid, (131)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[1(S)-[N-methyl-N-(1-iminoethyl)aminomethyl]3-methylbutylbenzoicacid, (132) 2′-(4-amidinophenylcarbamoyl)-4′-amino-4-(1(R),2,2-trimethylpropylcarbamoyl)-2-biphenylcarboxylic acid, (133)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[1-(1-iminoethyl)-4-(2-methylpropyl)piperidin-4-yl]carbamoyl]benzoicacid, (134)3-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-6-[(1(R),2,2-trimethylpropyl)carbamoyl]-2-pyridinecarboxylic acid, (135)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(t-butylcarbamoyl)benzoicacid, (136)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2,2-trichloroethylcarbamoyl)benzoicacid, (137)2-[3-(4-amidinophenylcarbamoyl)-2-thienyl]-6-(t-butylcarbamoyl)-2-pyridinecarboxylicacid, (138)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-(2,2,2-trifluoroethylcarbamoyl)benzoicacid, (139)2-[2-[(2-amidinopyrimidin-5-yl)carbamoyl]-6-methoxy-3-pyridyl]-5-(2,2-dimethylpropylcarbamoyl)benzoicacid, (140)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[1(S)-(2-aminoethyl)-3-mathylbutyl]carbamoyl]benzoicacid, (141)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2,2-dimethyl-3-hydroxypropyl)carbamoyl]benzoicacid, (142)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2,2-diethylbutyl)carbamoyl]benzoicacid, (143)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[((1-hydroxymethyl)cyclobutylmethyl)carbamoyl]benzoicacid, (144)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-ethyl-2-hydroxymethylbutyl)carbamoyf]benzoicacid, (145)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[((1-hydroxymethyl)cyclopentylmethyl)carbamoyl]benzoicacid, (146)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-propyl-2-hydroxymethylpentyl)carbamoyl]benzoicacid, (147)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-(2-methylpropyl)-2-hydroxymethyl-4-methylpentyl)carbamoyl]benzoicacid, (148)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1-hydroxymethylcyclopentyl)carbamoyl]benzoicacid, (149)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1-(2-methylpropyl)-1-hydroxymethyl-3-methylbutyl)carbamoyl]benzoicacid, (150)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-(hydroxymethyl)-2(S)-methylbutyl)carbamoyl]benzoicacid, (151)2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-isopropyl-3-aminopropyl)carbamoyl]benzoicacid, (152)2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-(2-aminoethyl)-3-methylbutyl)carbamoyl]benzoicacid, (153)2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-(2-aminoethyl)-2(S)-methylbutyl)carbamoyl]benzoicacid, (154)2′-(4-amidinophenylcarbamoyl)-4-[(1(S)-carboxymethyl-2,2-dimethylpropyl)carbamoyl]-2-biphenylcarboxylicacid, (155)2′-(4-amidinophenylcarbamoyl)-4-(1-carboxycyclopentylcarbamoyl)-2-biphenylcarboxylicacid, (156)2′-(4-amidinophenylcarbamoyl)-4-[(2-carboxy-2,2-dimethylethyl)carbamoyl]-2-biphenylcarboxylicacid, (157)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1(S)-carboxy-2-methylpropyl)carbamoyl]benzoicacid, (158)2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-carboxy-2-methylpropyl)carbamoyl]benzoicacid, (159)2′-(4-amidinophenylcarbamoyl)-4-[(1-carboxy-1-methylethyl)carbamoyl]-2-biphenylcarboxylicacid, (160)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[1(S)-(4-carboxyoxazol-2-yl)-3-methylbutyl)carbamoyl]benzoicacid, (161)2′-(4-amidinophenylcarbamoyl)-4-(2,2-dimethylcyclopentylcarbamoyl)-2-biphenylcarboxylicacid, (162)2′-(4-amidinophenylcarbamoyl)-4-[(N-methyl-N-t-butylamino)carbamoyl]-2-biphenylcarboxylicacid, (163)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(3-methyl-2-butenyl)carbamoyl]benzoicacid, (164)2′-(4-amidinophenylcarbamoyl)-5′-nitro-4-(2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxyiicacid, (165)3-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-6-[(1-isopropyl-2-methylpropyl)carbamoyl]-2-pyridinecarboxylicacid, (166)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (167)2′-[(2-amidino-5-pyridyl)carbamoyl]-4′-methoxy-4-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-biphenylcarboxylicacid, (168)2′-[(2-amidino-5-pyridyl)carbamoyl]-4-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-biphenylcarboxylicacid, (169)2-[4-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (170)2-[4-[(2-amidino-5-pyridyl)carbamoyl]-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (171)2-[2-(4-amidinophenylcarbamoyl)-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethyipropyl)carbamoyl]benzoicacid, (172)2-[2-[(2-amidino-5-pyridyl)carbamoyl]-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethyipropyl)carbamoyl]benzoicacid, (173)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (174)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-[(1(S)-hydroxymethyl-3-methylbutyl)carbamoyl]benzoicacid, (175)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-4-methyl-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (176)2-[3-(4-amidinophenylcarbamoyl)-2-thienyl]-5-[(1(S)-hydroxymethyl-2,2-dimethyipropyl)carbamoyl]benzoicacid, (177)2-[2-(4-amidinophenylcarbamoyl)-3-thienyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (178)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1-hydroxymethyl-1-methoxycarbonyl-3-methylbutyl)carbamoyl]benzoicacid, (179)2-[2-[N-(4-amidinophenyl)-N-methylcarbamoyl]-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyi)carbamoyl]benzoicacid, (180)2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (181)2-[2-(4-amidinophenylcarbamoyl)-6-isopropyloxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (182)2-[2-(4-amidinophenylcarbamoyl)-6-chloro-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (183)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-(2-hydroxyethyl)-2,2-dimethylpropyl)carbamoyl]benzoicacid, (184)3-[3-(4-amidinophenylcarbamoyl)-2-thienyl]-6-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-pyridinecarboxylicacid, (185)3-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-6-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-pyridinecarboxylicacid, (186)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[[1(S)-(2-hydroxyethyicarbamoyl)-3-methylbutyl]carbamoyl]benzoicacid, (187)3-[2-(2-amidino-5-pyridylcarbamoyl)-6-methoxy-3-pyridyl]-6-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-pyridinecarboxylicacid, (188)2-[2-(4-amidinophenylcarbamoyl)-6-dimethylamino-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (189)2-[2-(4-amidinophenylcarbamoyl)-6-butoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (190)2-[2-(2-amidinopyrimidin-5-yl)carbamoyl-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (191)2-[2-(4-amidinophenylcarbamoyl)-6-propoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, (192)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S),2-bishydroxymethyl-2-methylpropyl)carbamoyl]benzoic acid, (193)2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S),2-bishydroxymethyl-2-methylpropyl)carbamoyl]benzoic acid, (194)5-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-2-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-4-pyridinecarboxyficacid, (195)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2-methylpropyl)carbamoyl]benzoicacid, (196)2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-3,3-dimethylbutyl)carbamoyl]benzoicacid, (197)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-3,3-dimethylbutyl)carbamoyl]benzoicacid, (198)2′-(4-amidinophenylcarbamoyl)-4′-hydroxymethyl-4-(2-methylpropylcarbamoyl)-2-biphenylcarboxylicacid, (199)2′-(4-amidinophenylcarbamoyl)-4′-hydroxymethyl-4-(1,2,2-trimethylpropylcarbamoyl)-2-biphenylcarboxylicacid, (200)3-[2-(4-amidinophenylcarbamoyl)-4-methoxyphenyl]-6-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]-2-pyridinecarboxylicacid, (201)2-[2-(4-amidinophenylcarbamoyl)phenyl]-5-(2,2-dimethylpropylcarbamoyl)-3-furancarboxylicacid, (202)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(3-amino-1(S)-t-butylpropyl)carbamoyl]benzoicacid, (203)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1,1-bishydroxymethyl-2-methylpropyl)carbamoyl]benzoicacid, (204)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(4-(2-methylpropyl)-4-piperidino)carbamoyl]benzoicacid, (205)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-amino-3-methylbutyl)carbamoyl]benzoicacid, (206)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(1(S)-(4-aminobutylcarbamoyl)-3-methylbutyl)carbamoyl]benzoicacid, (207) 2-[2-(4-am idinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(3-amino-2,2-dimethylpropyl)carbamoyl]benzoicacid, (208)2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(3-amino-1(S)-t-butylpropyl)carbamoyl]benzoicacid, (209)2-[2-(4-amidinophenylcarbamoyl)-6-ethoxy-3-pyridyl]-5-[(4-amino-1(S)-t-butylbutyl)carbamoyl]benzoicacid, (210) N-hydroxy-2′-(4-amidinophenylcarbamoyl)-4-[(1(R),2,2-trimethylpropyl)carbamoyl]-2-biphenylcarboxamide, (211)2′-(4-amidinobenzyloxy)-4-(2-methylpropylcarbamoyl)-2-biphenylcarboxylicacid, (212)2′-(4-amidinobenzyloxy)-4-(1(S)-hydroxymethyl-2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylicacid, (213)2′-(4-amidinobenzyioxy)-4′-methyl-4-(1(S)-hydroxymethyl-2,2-dimethylpropylcarbamoyl)-2-biphenylcarboxylicacid, (214)2′-(4-amidinophenylaminomethyl)-4-(1(S)-hydroxymethyl-2,2-dimethylpropyicarbamoyl)-2-biphenylcarboxylicacid, (215)2-[2-(4-amidinophenylaminomethyl)-3-pyridyl]-5-(2-methylpropylcarbamoyl)benzoicacid, (216)2-[2-(4-amidinophenylaminomethyl)-6-methyl-3-pyridyl]-5-(2-methylpropylcarbamoyl)benzoicacid, (217)2-[4-(4-amidinophenylaminomethyl)-3-pyridyl]-5-(2-methylpropylcarbamoyl)benzoicacid, methyl ester, ethyl ester, benzyl ester thereof, non-toxic saltsthereof or hydroxide thereof.
 8. A compound according to claim 1, whichis selected from (1)2′-(4-amidinophenylcarbamoyl)-4′-methyl-2-biphenylcarboxylic acid, (2)2′-(4-amidinophenylcarbamoyl)-4′-((1-carboxy-2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (3) 2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxylic acid, (4)2,3-dihydro-2,2-dimethyl-5-(2-(4-amidinophenylcarbamoyl)phenyl)-6-benzofurancarboxylicacid, (5) 2′-(4-amidinophenylcarbamoyl)-2,3-biphenyldicarboxylic acid,(6) 2′-(4-amidinophenylcarbamoyl)-6-methyl-2-biphenylcarboxylic acid,(7) 2′-(4-amidinophenylcarbamoyl)-5-methoxy-2-biphenylcarboxylic acid,(8) 2′-(4-amidinophenylcarbamoyl)-4-methoxy-2-biphenylcarboxylic acid,(9) 2′-(4-amidinophenylcarbamoyl)-6-methoxy-2-biphenylcarboxylic acid,(10) 2′-(4-amidinophenylcarbamoyl)-4-hydroxy-2-biphenylcarboxylic acid,(11) 2′-(4-amidinophenylcarbamoyl)-5-hydroxy-2-biphenylcarboxylic acid,(12) 2′-(4-amidinophenylcarbamoyl)-5-methyl-2-biphenylcarboxylic acid,(13) 2′-(4-amidinophenylcarbamoyl)-4-methyl-2-biphenylcarboxylic acid,(14) 2′-(4-amidinophenylcarbamoyl)-3-hydroxy-2-biphenylcarboxylic acid,(15)2′-(4-amidinophenylcarbamoyl)-4′-methyl-5-chloro-2-biphenylcarboxylicacid, (16) 2′-(4-amidinophenylcarbamoyl)-3-methoxy-2-biphenylcarboxylicacid, (17)2′-(4-amidinophenylcarbamoyl)-4′-methyl-4-methoxy-2-biphenylcarboxyicacid, (18)2-(2-(4-amidinophenylcarbamoyl)phenyl)-1-naphthalenecarboxylic acid,(19) 2′-(4-amidinophenylcarbamoyl)-3-methyl-2-biphenylcarboxylic acid,(20)3-(2-(4-amidinophenylcarbamoyl)phenyl)-7-methoxy-2-naphthalenecarboxylicacid, (21)3-(2-(4-amidinophenylcarbamoyl)phenyl)-5-methoxy-2-naphthalenecarboxylicacid, (22) 2′-(4-amidinophenylcarbamoyl)-2,4-biphenyldicarboxylic acid,(23)3-(2-(4-amidinophenylcarbamoyl)phenyl)-6-methoxy-2-naphthalenecarboxylicacid, (24)3-(2-(4-amidinophenylcarbamoyl)phenyl)-8-methoxy-2-naphthalenecarboxylicacid, (25)2′-(4-amidinophenylcarbamoyl)-3,4-dimethoxy-2-biphenylcarboxylic acid,(26)6-(2-(4-amidinophenylcarbamoyl)phenyl)-1,2-methylenedioxybenzen-5-carboxylicacid, (27) 2′-(4-amidinophenylcarbamoyl)-4′-nitro-2-biphenylcarboxylicacid, (28) 2′-(4-amidinophenylcarbamoyl)-2-biphenylphosphoric acid, (29)2′-(4-amidinophenylcarbamoyl)-4-fluoro-2-biphenylcarboxyiic acid, (30)2′-(4-amidinophenylcarbamroy)-4-(2-methoxycarbonylethyl)-2-biphenylcarboxylicacid, (31)2′-(4-amidinophenylcarbamoyl)-4-(2-methoxyethoxy)-2-biphenylcarboxylicacid, (32)2′-(4-amidinophenylcarbamoyl)-4-trifluoromethoxy-2-biphanylcarboxylicacid, (33)3-(2-(4-amidinophenylcarbamoyl)phenyl)-8-(2-methoxyethoxy)-2-naphthalenecarboxylicacid, (34)2′-(4-amidinophenylcarbamoyl)-4-((isopropyicarbonyl)aminomethyl)-2-biphenylcarboxylicacid, (35)2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyi)sulfamoyl)-2-biphenylcarboxylicacid, (36) 2′-(4-amidinophenylcarbamoyl)-5-chloro-2-biphenylcarboxylicacid, (37)3-(2-(4-amidinophenylcarbamoyl)phenyl)-2-naphthalenecarboxylic acid,(38) 2′-(3-amidinophenylcarbamoyl)-2-biphenyl(carboxylic acid, (39)2-(2-(4-amidinophenylcarbamoyl)phenyl)cinnamic acid, (40)2′-(4-amidinophenylcarbamoyl)biphenyl-2-yloxyacetic acid, (41)3-(2-(4-amidinophenylcarbamoyl)-4-methyiphenyl)-2-naphthalenecarboxylicacid, (42)1(2-(4-amidinophenylcarbamocyl)phanyl)-2-naphthalenecarboxylic acid,(43)3-(2-(4-amidinophenylcarbamoyl)-4-methoxyphenyl)-2-naphthalenecarboxylicacid, (44)3-(2-(4-amidinophenylcarbamoyl)-4-propoxyphenyl)-2-naphthalenecarboxylicacid, (45) 2′-(4-amidinophenylcarbamoyl)-4-nitro-2-biphenylcarboxylicacid, (46)2′-(4-amidinophenylcarbamoyl)-4-methylsulfonylamino-2-biphenylcarboxyiiciacid, (47) 2′-(4-amidinophenylcarbamoyl)-4-chloro-2-biphenylcarboxylicacid, (48) 2′-(4-amidinophenylcarbamoyl)biphenyl-2-yiacetic acid, (49)2′-(4-amidinophenylcarbamoyl)-5-nitro-2-biphenylcarboxylic acid, (50)2′-(4-amidinophenylcarbamoyl)-4-mathylaminomethyl-2-biphenylcarboxylicacid, (51)2′-(4-amidinophenylcarbamnoyl)-4-ethoxycarbonylmethoxy-2-biphanylcarboxylicacid, (52) 2′-(4-amidinophenylcarbamoyl)-4-(2-(methoxymethoxy)ethoxy)-biphenylcarboxylic acid,(53)3-(2-(4-amidinophenylcarbamoyl)phenyl)-5-methoxymethoxcy-2-naphthalenecarboxylicacid, (54)3-(2-(4-amidinophenylcarbamoyl)phenyl)-8-methoxymethoxy-2-naphthaienecarboxylicacid, (55) 2′-(4-amidinophenylcarbamoyl)-4′-amino-2-biphenyl carboxylicacid, (56) 2′-(4-amidinophenylcarbamoyl)-4′-chloro-2-biphenylcarboxylicacid, (57)2′-(4-amidinophenylcarbamoyl)-4′-(2-methoxycarbonylethyl)-2-biphenylcarboxylicacid, (58)2′-(4-amidinophenylcarbamoyl)-3′-benzyloxy-2-biphenylcarboxylic acid,(59) 2′-(4-amidinophenylcarbamoyl)-6′-methyl-2-biphenylcarboxylic acid,(60) 2′-(4-amidinophenylcarbamoyl)-5′-methyi-2-biphenylcarboxylic acid,(61) 2′-(4-amidinophenylcarbamoyl)-4′-isopropyl-2-biphenylcarboxylicacid, (62) 2′-(4-amidinophenylcarbamoyl)-4′-t-butyl-2-biphenylcarboxylicacid, (63) 2′-(4-amidinophenylcarbamoyl)-4′-ethyl-2-biphenylcarboxylicacid, (64) 2′-(4-amidinophenylcarbamoyl)-4′-methoxy-2-biphenylcarboxyiicacid, (65) 2′-(4-amidinophenylcarbamoyl)-4′-ciano-2-biphenylcarboxylicacid, (66) 2′-(4-amidinophenylcarbamoyl)-5′-methoxy-2-biphenylcarboxylicacid, (67) 2′-(4-amidinophenylcarbamoyl)-6′-methoxy-2-biphenylcarboxylicacid, (68)2′-(4-amidinophenylcarbamoyl)-5′-chloro-4-methyl-2-biphenylcarboxylicacid, (69)2′-(4-amidinophenylcarbamoyl)-4′-methoxy-4-methyl-2-biphenylcarboxylicacid, (70)2′-(4-amidinophenylcarbamoyl)-4′-dimethylcarbamoyl-2-biphenylcarboxylicacid, (71) 2′-(4-amidinophenylcarbamoyl)-2,4′-biphenyldicarboxylic acid,(72)2′-(4-amidinophenylcarbamoyl)-4′-methylcarbamoyl-2-biphenylcarboxylicacid, (73)2′-(4-amidinophenylcarbamoyl)-4′-methyiaminomethyl-2-biphenylcarboxylicacid, (74)2′-(4-amidinophenylcarbamoyl)-4′-(2-hydroxyethoxy)-2-biphenylcarboxylicacid, (75) 2′-(4-amidinophenylcarbamoyl)-4′-fluoro-2-biphenylcarboxylicacid, (76)2′-(4-amidinophenylcarbamoyl)-4′-(2-methoxyethoxy)-2-biphenylcarboxylicacid, (77)2′-(4-amidinophenylcarbamoyl)-4′-trifluoromethoxy-2-biphenylcarboxylicacid, (78)2′-(4-amidinophenylcarbamoyl)-4′-((methoxycarbonylmethyl)carbamoyl)-2-biphenylcarboxyiicacid, (79)2′-(4-amidinophenylcarbamoyl)-4′-((1-methoxycarbonyl-2-phenylethyl)carbamoyl)-2-biphenylcarboxyticacid, (80)2′-(4-amidinophenylcarbamoyl)-4′-ethoxycarbonylmethoxy-biphenylcarboxylicacid, (81) 2′-(4-amidinophenylcarbamoyl)-4′-hydroxy-2-biphenylcarboxylicacid, (82) 2′-(4-amidinophenylcarbamoyl)-5′-hydroxy-2-biphenylcarboxylicacid, (83) 2′-(4-amidinophenylcarbamoyl)-4′-bromo-2-biphenylcarboxylicacid, (84) 2′-(4-amidinophenylcarbamoyl)-4-bromo-2-biphenylcarboxylicacid, (85) 2′-(4-amidinophenylcarbamoyl)-3′-methoxy-2-biphenylcarboxylicacid, (86) 2′-(4-amidinophenylaminomethyl)-2-biphenylcarboxylic acid,(87) 2′-(4-amidinophenylaminomethyl)-4′-methoxy-2-biphenylcarboxylicacid, (88) 2′-(4-(N²-t-butoxycarbonyloxyamidino)phenylcarbamoyl)-2-biphenylcarboxylicacid, (89)2′-(4-(N²-ethoxycarbonylamidino)phenylcarbamoyl)-2-biphenylcarboxylicacid, (90) 2-(2-(4-amidinophenylcarbamoyl)pyridin-3-yl)benzoic acid,(91)2′-(4-amidinophenylcarbamoyl)-4-(3-methylbutoxy)-2-biphenylcarboxylicacid, (92)2′-(4-amidinophenylcarbamoyl)-4-methylaminomethyl-2-biphenylcarboxylicacid, (93)2′-(4-amidinophenylcarbamoyl)-4-carboxymethoxy-2-biphenylcarboxylicacid, (94)2′-(4-amidinophenylcarbamoyl)-4-(2-hydroxyethoxy)-2-biphenylcarboxylicacid, (95)3-(2-(4-amidinophenylcarbamoyl)phenyl)-5-hydroxy-2-naphthalenecarboxylicacid, (96)3-(2-(4-amidinophenylcarbamoyl)phenyl)-8-hydroxy-2-naphthalenecarboxylicacid, (97)2′-(4-amidinophenylcarbamoyl)-4-((2-methylpropyl)aminomethyl)-2-biphenylcarboxylicacid, (98) 2′-(4-amidinophenylcarbamoyl)-3′-hydroxy-2-biphenylcarboxylicacid, (99)2′-(4-amidinophenylcarbamoyl)-4′-((carboxymethyl)carbamoyl)-2-biphenylcarboxylicacid, (100)2′-(4-amidinophenylcarbamoyl)-4′-((1-carboxy-2-phenylethyl)carbamoyl)-2-biphenylcarboxylicacid, (101)2′-(4-amidinophenylcarbamoyl)-4′-carboxymethoxy-2-biphenylcarboxylicacid, (102)2′-(4-(N²-hydroxyamidino)phenylcarbamoyl)-2-biphenylcarboxylic acid,(103) N-hydroxy-2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxamide,(104)N-hydroxy-N-methyl-2′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxamide,(105)N-hydroxy-2′-(4-amidinophenylcarbamoyl)-4′-methyl-2-biphenylcarboxamide,(106)N-hydroxy-2′-(4-amidinophenylcarbamoyl)-4′-methoxy-2-biphenylcarboxamide,(107) N-hydroxy-2′-(4-(N²-ethoxycarbonylamidino)phenylcarbamoyl)-2-biphenylcarboxamide, (108)2′-(4-amidinophenylcarbamoyl)-4-amino-2-biphenylcarboxylic acid, (109)3-(2′-(4-amidinophenylcarbamoyl)biphenyl-2-yl)propanoic acid, (110)2′-(4-amidinophenylcarbamoyl)-4-methylcarbonylamino-2-biphenylcarboxylicacid, (111)2′-(4-amidinophenylcarbamoyl)-4′-methyicarbonylamino-2-biphenylcarboxylicacid, (112)2′-(4-amidinophenylcarbamoyl)-4-((2-methyipropylcarbonyl)amino)-2-biphenylcarboxylicacid, (113)N-hydroxy-2′-(4-(N²-hydroxyamidino)phenylcarbamoyl)-2-biphenylcarboxamide,(114)2′-(4-(N²-propenyl)oxycarbonylamidino)phenylearbamoyl)-2-biphenylcarboxylicacid, (115)2′-(1-(4-amidinophenylamino)-1-methoxycarbonylmethyl)-2-biphenylcarboxylicacid, (116)2′-(1-(4-amidinophenylamino)-1-methylcarbamoylmethyl)-2-biphenylcarboxylicacid, (117)2′-(1-(4-amidinophenylamino)-1-cianomethyl)-2-biphenylcarboxylic acid,(118) 2′-(1-(4-amidinophenylamino)-1-carboxymethyl)-2-biphenylcarboxylicacid, (119) 2′-(4-amidinobenzyloxy)-2-biphenylcarboxylic acid, (120)2′-(4-amidinophenylcarbamoyl)-2-(tetrazol-5-yl)biphenyl, (121)2-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]-5-(2,2-dimethylpropyloxycarbonyl)benzoicacid, (122)4-[2-(4-amidinophenylcarbamoyl)-6-methyl-3-pyridyl]isophthalic acid,(123) 4-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]isophthalicacid, (124)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[1-(2,2-dimethylpropyl)tetrazol-5-yl]benzoic acid, (125)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5[(2,2-diethylbutyloxy)carbamoyl]benzoicacid, (126)2′-(4-amidinophenylcarbamoyl)-4-(3-methylbutylcarbonyl)-2-biphenylcarboxylicacid, (127)2-[2-(4-amidinophenylcarbamoyl)-6-methoxy-3-pyridyl]-5-[(2-amino-2-hydroxymethyl-3-methylbutyl)carbamoyl]benzoicacid, methyl ester, ethyl ester, benzyl ester thereof, non-toxic saltsthereof or hydroxide thereof.
 9. A compound according to claim 1, whichis selected from (1) 3-(4-amidinophenylcarbamoyl)-4-biphenycarboxylicacid, (2) 4-(4-amidinophenylcarbamoyl)-3-biphenylcarboxylic acid, (3)3′-(4-amidinophenylcarbamoyl)-2-biphenylcarboxylic acid, (4)2′-(4-amidinophenylcarbamoyl)-3-biphenylcarboxylic acid, (5)2′-(4-amidinophenylcarbamoyl)-4-biphenylcarboxylic acid, (6)2′-(4-amidinophenoxymethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (7)2′-(4-amidinophenylthiomethyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (8)2′-(4-amidinophenylethynyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (9) 2′-(4-amidinophenylethynyl)-2-biphenylcarboxylic acid, (10)2′-((1E)-2-(4-amidinophenyl)ethenyl)-4-((2-methylpropyl)carbamoyl)-2-biphenylcarboxylicacid, (11) 2′-((1E)-2-(4-amidinophenyl)ethenyl)-2-biphenylcarboxylicacid, (12)2′-(2-(4-amidinophenyl)ethyl)-4-((2-methyipropyl)carbamoyl)-2-biphenylcarboxylicacid, (13) 2′-(2-(4-amidinophenyl)ethyl)-2-biphenylcarboxylic acid, (14)2-[2-(4-amidinophenoxycarbonyl)-6-methoxy-3-pyridyl]-5-[(1(S)-hydroxymethyl-2,2-dimethylpropyl)carbamoyl]benzoicacid, methyl ester, ethyl ester, benzyi ester thereof, non-toxic saltsthereof or hydroxide thereof.
 10. A compound according to claim 1, whichis selected from (1)2-(3-(4-amidinophenylcarbamoyl(napthalen-2-yl)benzoic acid), (2)2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-((1-methoxycarbonyl-2-methylpropyl)carbamoyl)benzoicacid, (3)2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-((2-methylpropyl)carbamoyl)benzoicacid, (4)2-(3-(4-amidinophenylcarbamoyl)-6-methoxynaphthalen-2-yl)benzoic acid,(5) 2-(3-(4-amidinophenylcarbamoyl)-7-methoxynaphthalen-2-yl)benzoicacid, (6)2-(3-(4-amidinophenylcarbamoyl)-5-methoxynaphthalen-2-yl)benzoic acid,(7) 2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-methylbenzoicacid, (8) 2-(2-(4-amidinophenylcarbamoyl)naphthalen-1-yl) benzoic acid,(9) 2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-methoxybenzoicacid, (10)2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-propoxybenzoic acid,(11)2-(2,3-dihydro-2,2-dimethyl-6-(4-amidinophenylcarbamoyl)benzofuran-5-yl)benzoicacid, (12)2-(5,6,7,8-tetrahydro-3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)benzoicacid, (13) 2-(6-(4-amidinophenylcarbamoyl)indan-5-yl)benzoic acid, (14)2-(3-(4-amidinophenylcarbamoyl)-8-methoxynaphthalen-2-yl)benzoic acid,(15)2-(6-(4-amidinophenylcarbamoyl)-1,2-methylenedioxybenzen-5-yl)benzoicacid, (16)2-(3-(4-amidinophenylcarbamoyl)-8-hydroxynaphthalen-2-yl)benzoic acid,(17)2-(3-(4-amidinophenylcarbamoyl)-5-(2-methoxyethoxy)naphthalen-2-yl)benzoicacid, (18)2-(3-(4-amidinophenylcarbamoyl)-5-hydroxynaphthalen-2-yl)benzoic acid,(19)2-(6-(4-amidinophenylcarbamoyl)-1-benzyfoxymethylbenzimidazol-5-yl)benzoicacid, (20)2-(5-(4-amidinophenylcarbamoyl)-1-benzyloxymethylbenzimidazol-6-yl)benzoicacid, (21) 2-(6-(4-amidinophenylcarbamoyl)benzofuran-5-yl)benzoic acid,(22) 2-(5-(4-amidinophenylcarbamoyl)benzofuran-6-yl)benzoic acid, (23)2-(3-(4-amidinophenylaminomethyl)naphthalen-2-yl)benzoic acid, (24)2-(3-(4-amidinophenylaminomethyl)naphthalen-2-yl)-5-((2-methylpropyl)carbamoyl)benzoicacid, (25) 2-(2-(4-amidinophenylcarbamoyl)benzothiophene-3-yl)benzoicacid, (26)2-(3-(4-amidinophenylcarbamoyl)-5-methoxybenzofuran-2-yl)benzoic acid,(27) 2-(6-(4-amidinophenylcarbamoyl)benzimidazol-5-yl)benzoic acid, (28)N-hydroxy-2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-((2-methylpropyl)carbamoyl)benzcarboxamide,(29)N-hydroxy-2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)benzcarboxamide,(30)N-hydroxy-2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-methoxybenzcarboxamide,(31) 2-(6-(4-amidinophenylcarbamoyl)isoquinolin-7-yl)benzoic acid,methyl ester, ethyl ester, benzyl ester thereof, non-toxic salts thereofor hydroxide thereof.
 11. A blood coagulation factor VIIa inhibitorcomposition comprising a compound according to claim 1, as activeingredient.
 12. A method for the prevention and/or treatment ofangiopathy in a patient said method comprising administering to saidpatient an effective amount of an amidino compound of the formula (I) asdefined in claim 1, non-toxic salts thereof or hydrates thereof asactive ingredient.
 13. The method according to claim 12 wherein saidangiopathy is selected from the group consisting of disseminatedintravascular coagulation, coronory thrombosis, cerebral infarction,cerebral embolism, deep venous thrombosis, peripheral arterialobstruction, thrombosis after artificial vascular transplantation andartificial valve transplantation, post-operative thrombosis,re-obstruction and restonsis after coronary artery bypass operation,re-obstruction and restonsis after PTCA (percutaneous transluminalcoronary angioplasty) or TRCP (percutaneous transluminal coronaryangioplasty), thrombosis by extracorporeal circulation andprocoagulative diseases.
 14. The method according to claim 12, whereinthe anigopathy is a pulmonary disease selected from the group consistingof pulmonary infarction and pulmonary embolism.
 15. A method accordingto claim 13, wherein procoagulative disease is glomerlonephritis.